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Priego-Parra BA, Gallego-Durán R, Román-Calleja BM, Velarde-Ruiz Velasco JA, Romero-Gómez M, Gracia-Sancho J. Advancing precision medicine in metabolic dysfunction-associated steatotic liver disease. Trends Endocrinol Metab 2025:S1043-2760(25)00052-9. [PMID: 40221323 DOI: 10.1016/j.tem.2025.03.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 03/11/2025] [Accepted: 03/17/2025] [Indexed: 04/14/2025]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), has become a pressing global health concern. The complexity of MASLD and the lack of universally effective treatments expose the limitations of current interventions, which focus mainly on lifestyle modifications. Here, we explore the multilayered nature of MASLD, emphasizing its pathophysiology in shaping future medical and lifestyle interventions from a personalized medicine perspective, based on individual molecular profiles. Additionally, we address the limitations of current animal models in reflecting human metabolic syndrome and sex-specific differences. We argue that a holistic approach, integrating social determinants of health, patient preferences, and adherence patterns, is essential for advancing MASLD management effectively.
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Affiliation(s)
- Bryan A Priego-Parra
- Instituto de Investigaciones Médico-Biológicas, Universidad Veracruzana, Veracruz, Mexico; Centro de Investigaciones Biomédicas, Universidad Veracruzana, Veracruz, Mexico
| | - Rocío Gallego-Durán
- UCM Digestive Diseases, Virgen del Rocío University Hospital. SeLiver Group, Instituto de Biomedicina de Sevilla (HUVR/CSIC/US), Department of Medicine, University of Seville, Seville, Spain; Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Berenice M Román-Calleja
- División de Hepatología, Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, Mexico
| | | | - Manuel Romero-Gómez
- UCM Digestive Diseases, Virgen del Rocío University Hospital. SeLiver Group, Instituto de Biomedicina de Sevilla (HUVR/CSIC/US), Department of Medicine, University of Seville, Seville, Spain; Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Jordi Gracia-Sancho
- Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain; Liver Vascular Biology Lab, IDIBAPS - Hospital Clínic de Barcelona, Spain; Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland.
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Kobayashi Y, Yamashita Y, Kimura T, Iwadare T, Okumura T, Wakabayashi SI, Kobayashi H, Sugiura A, Joshita S, Umemura T. Hormone replacement therapy for steatotic liver management after surgical menopause. Clin J Gastroenterol 2025; 18:352-356. [PMID: 39760964 DOI: 10.1007/s12328-024-02090-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 12/18/2024] [Indexed: 01/07/2025]
Abstract
Although steatotic liver onset after natural menopause has been reported, evidence on the clinical course and treatment options for steatotic liver after surgical menopause is scarce. A 34-year-old woman with a history of severe obesity presented to our department with liver dysfunction following total hysterectomy and bilateral oophorectomy. Her serum estradiol level was notably low at 22 pg/mL, and a liver biopsy revealed significant fatty degeneration, lobular inflammation, hepatocyte ballooning, and stage F1 fibrosis. These findings supported a diagnosis of steatotic liver disease following surgical menopause. Subsequent initiation of hormone replacement therapy (HRT) with estrogen led to rapid improvements in liver function and steatotic liver symptoms. Steatotic liver disease should be considered in cases of liver impairment in postoperative menopausal patients, for which HRT represents a promising treatment option.
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Affiliation(s)
- Yoshiaki Kobayashi
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Yuki Yamashita
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan.
- Consultation Center for Liver Diseases, Shinshu University Hospital, Matsumoto, Japan.
| | - Takefumi Kimura
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
- Consultation Center for Liver Diseases, Shinshu University Hospital, Matsumoto, Japan
| | - Takanobu Iwadare
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Taiki Okumura
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Shun-Ichi Wakabayashi
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Hiroyuki Kobayashi
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Ayumi Sugiura
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Satoru Joshita
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Takeji Umemura
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
- Consultation Center for Liver Diseases, Shinshu University Hospital, Matsumoto, Japan
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Iborra I, Bartoli R, Bargalló A, Sunyé S, Ardèvol A, Fortuny M, Capdevila S, Masnou H, Morillas RM. Impact of sex differences on the induction and evolution of clinical signs of an end-stage liver disease rat model. Lab Anim 2025:236772241309760. [PMID: 40079644 DOI: 10.1177/00236772241309760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/15/2025]
Abstract
BackgroundHistorically, preclinical studies with rat models have been carried out only with male animals. Current regulations require sex parity in experimental procedures. Several studies have shown significant sex differences in rat models of liver fibrosis, but there is no data available in end-stage liver disease. The aim was to describe sex-related differences in a carbon tetrachloride (CCl4)-induced rat model of cirrhosis with ascites.MethodsFifty-two rats, 26 of each sex, fed ad libitum with phenobarbital-enriched drinking water (5 mmol/l). CCl4 was administered orally weekly, adjusting doses to weight changes after CCl4 administration until ascites development.ResultsMedian time to ascites development was significantly higher in females (19 vs. 10 weeks). Males showed significantly greater weight changes 48 h after CCl4 administration. The cumulative dose of CCl4 was significantly higher in females, both at the time of diagnosis of ascites (10.7 vs. 1.5 ml) and at week 10 (median time to ascites development in males) (3.9 vs. 1.5 ml). There were no significant sex differences in model associated mortality (31% males vs. 27% females).ConclusionsSex differences have a significant impact on CCl4-induced end-stage liver disease; classical models should be redesigned to appropriately encompass both sexes.
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Affiliation(s)
- Ignacio Iborra
- Hepatology Unit, Gastroenterology Department, Germans Trias i Pujol University Hospital, Badalona, Spain
- Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain
- Medicine Department, Universitat Autònoma de Barcelona (UAB), Spain
| | - Ramon Bartoli
- Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain
- CIBER de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain
| | - Ana Bargalló
- EndosMedicina, Gastroenterology Department, HM Nou Delfos Hospital, Barcelona, Spain
| | - Sergi Sunyé
- Comparative Medicine and Bioimage Centre of Catalonia (CMCiB), Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain
| | - Alba Ardèvol
- Hepatology Unit, Gastroenterology Department, Germans Trias i Pujol University Hospital, Badalona, Spain
| | - Marta Fortuny
- Hepatology Unit, Gastroenterology Department, Germans Trias i Pujol University Hospital, Badalona, Spain
- Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain
- Medicine Department, Universitat Autònoma de Barcelona (UAB), Spain
| | - Sara Capdevila
- Comparative Medicine and Bioimage Centre of Catalonia (CMCiB), Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain
| | - Helena Masnou
- Hepatology Unit, Gastroenterology Department, Germans Trias i Pujol University Hospital, Badalona, Spain
- Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain
- CIBER de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain
| | - Rosa M Morillas
- Hepatology Unit, Gastroenterology Department, Germans Trias i Pujol University Hospital, Badalona, Spain
- Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain
- Medicine Department, Universitat Autònoma de Barcelona (UAB), Spain
- CIBER de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain
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Manjarrés L, Xavier A, González L, Garrido C, Zacconi FC, Rivera K, Parra L, Phinikaridou A, Besa C, Andia ME. Sex differences in the relationship between body composition and MASLD progression in a murine model of metabolic syndrome. iScience 2025; 28:111863. [PMID: 39991541 PMCID: PMC11847041 DOI: 10.1016/j.isci.2025.111863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 11/30/2024] [Accepted: 01/03/2025] [Indexed: 02/25/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) progression exhibits significant sex differences, with males generally developing more severe disease. This study used an endothelial nitric oxide synthase knockout (eNOS KO) murine model to investigate sex-specific MASLD progression under a Western diet intervention. Magnetic resonance imaging (MRI) assessed body composition and liver and skeletal muscle fat fraction, revealing greater visceral fat, liver volume, and liver-to-muscle fat ratios in males. Dimensionality reduction and clustering analyses identified distinct sex-specific MASLD phenotypes and progression patterns. Histological evaluations confirmed greater liver damage in males, evidenced by higher MAFLD Activity Scores. These findings highlight the critical role of sex as a biological variable in MASLD pathology and emphasize the influence of body composition and fat distribution on disease progression. The study underscores the utility of advanced imaging and analytical techniques for refining non-invasive diagnostics and guiding sex-specific interventions, paving the way for personalized MASLD management strategies.
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Affiliation(s)
- Laura Manjarrés
- PhD Program in Medical Sciences, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile
- Millennium Institute for Intelligent Healthcare Engineering, i-Health, Santiago, Chile
| | - Aline Xavier
- Faculty of Engineering, Universidad de Santiago de Chile, Santiago, Chile
| | - Leticia González
- Millennium Institute for Intelligent Healthcare Engineering, i-Health, Santiago, Chile
- Biomedical Imaging Center and Radiology Department, School of Medicine. Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Camila Garrido
- Millennium Institute for Intelligent Healthcare Engineering, i-Health, Santiago, Chile
- Faculty of Chemistry and Pharmacy, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Flavia C. Zacconi
- Faculty of Chemistry and Pharmacy, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Katherine Rivera
- Millennium Institute for Intelligent Healthcare Engineering, i-Health, Santiago, Chile
| | - Laura Parra
- Millennium Institute for Intelligent Healthcare Engineering, i-Health, Santiago, Chile
| | - Alkystis Phinikaridou
- School of Biomedical Engineering and Imaging Sciences, King’s College London, London, UK
| | - Cecilia Besa
- Millennium Institute for Intelligent Healthcare Engineering, i-Health, Santiago, Chile
- Biomedical Imaging Center and Radiology Department, School of Medicine. Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Marcelo E. Andia
- Millennium Institute for Intelligent Healthcare Engineering, i-Health, Santiago, Chile
- Biomedical Imaging Center and Radiology Department, School of Medicine. Pontificia Universidad Católica de Chile, Santiago, Chile
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Zhang JW, Zhang N, Lyu Y, Zhang XF. Influence of Sex in the Development of Liver Diseases. Semin Liver Dis 2025. [PMID: 39809453 DOI: 10.1055/a-2516-0261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/16/2025]
Abstract
The liver is a sexually dimorphic organ. Sex differences in prevalence, progression, prognosis, and treatment prevail in most liver diseases, and the mechanism of how liver diseases act differently among male versus female patients has not been fully elucidated. Biological sex differences in normal physiology and disease arise principally from sex hormones and/or sex chromosomes. Sex hormones contribute to the development and progression of most liver diseases, with estrogen- and androgen-mediated signaling pathways mechanistically involved. In addition, genetic factors in sex chromosomes have recently been found to contribute to the sex disparity of many liver diseases, which might explain, to some extent, the difference in gene expression pattern, immune response, and xenobiotic metabolism between men and women. Although increasing evidence suggests that sex is one of the most important modulators of disease prevalence and outcomes, at present, basic and clinical studies have long been sex unbalanced, with female subjects underestimated. As such, this review focuses on sex disparities of liver diseases and summarizes the current understanding of sex-specific mechanisms, including sex hormones, sex chromosomes, etc. We anticipate that understanding sex-specific pathogenesis will aid in promoting personalized therapies for liver disease among male versus female patients.
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Affiliation(s)
- Jie-Wen Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
- Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
- National-Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
| | - Nan Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
- Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
- National-Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
| | - Yi Lyu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
- Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
- National-Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
| | - Xu-Feng Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
- Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
- National-Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
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Tong X, Sun Y, Wang Q, Zhao X, Chen W, Zhang M, Ren Y, Zhao X, Wu X, Zhao J, Sun C, Zheng M, Ren H, Yang Z, Ou X, Jia J, You H. Delicate and thin fibrous septa indicate a regression tendency in metabolic dysfunction-associated steatohepatitis patients with advanced fibrosis. Hepatol Int 2025; 19:166-180. [PMID: 39152361 DOI: 10.1007/s12072-024-10719-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 08/02/2024] [Indexed: 08/19/2024]
Abstract
BACKGROUND AND AIMS Metabolic dysfunction-associated steatohepatitis (MASH)-related fibrosis is reversible. However, the dynamic morphology change in fibrosis regression remains unclear. We aim to explore the morphological characteristics of fibrosis regression in advanced MASH patients. METHODS Clinical and histological data of 79 biopsy-proved MASH patients with advanced fibrosis (F3-F4) were reviewed. The second harmonic generation/two-photon excitation fluorescence (SHG/TPEF) image technology was used to quantitatively identify the R (regressive) septa from P (progressive) septa and PS (perisinusoidal) fibrosis. Non-invasive tests were used to compare the fibrosis level with and without R septa groups. Transcriptomics was used to explore hub genes and the underlying mechanism of the formation of R septa. RESULTS The R septa were different from the P septa and PS fibrosis in detail collagen quantitation identified by SHG/TPEF technology. The R septa were found in MASH fibrosis-regressed patients, which met the definition of the "Beijing classification". Therefore, patients were divided into two groups according to septa morphology: with R septa (n = 10, 12.7%), and without R septa (n = 69, 87.3%). Patients with R septa had lower values in most non-invasive tests, especially for liver stiffness assessed by TE (12.3 vs. 19.4 kPa, p = 0.010) and FAST (FibroScan®-AST) score (0.43 vs. 0.70, p = 0.003). Transcriptomics analysis showed that the expressions of five hub fibrogenic genes, including Col3A1, BGN, Col4A1, THBS2, and Col4A2 in the R septa group, were significantly lower. CONCLUSIONS The R septa can be differentiated from the P septa and PS fibrosis by quantitative assessment of SHG/TPEF, and it represents a tendency of fibrosis regression in MASH patients. TRIAL REGISTRATION NCT03386890, 29/12/2017.
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Affiliation(s)
- Xiaofei Tong
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, 95 Yong-An Road, Xi-Cheng District, Beijing, 100050, China
| | - Yameng Sun
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, 95 Yong-An Road, Xi-Cheng District, Beijing, 100050, China
| | - Qianyi Wang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, 95 Yong-An Road, Xi-Cheng District, Beijing, 100050, China
| | - Xinyan Zhao
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, 95 Yong-An Road, Xi-Cheng District, Beijing, 100050, China
| | - Wei Chen
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, 95 Yong-An Road, Xi-Cheng District, Beijing, 100050, China
| | - Mengyang Zhang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, 95 Yong-An Road, Xi-Cheng District, Beijing, 100050, China
| | - Yayun Ren
- HistoIndex Pte Ltd, Singapore, Singapore
| | - Xinyu Zhao
- Clinical Epidemiology and EBM Unit, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, 95 Yong-An Road, Xi-Cheng District, Beijing, 100050, China
| | - Xiaoning Wu
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, 95 Yong-An Road, Xi-Cheng District, Beijing, 100050, China
| | - Jingjie Zhao
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, 95 Yong-An Road, Xi-Cheng District, Beijing, 100050, China
| | - Chenglin Sun
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, 95 Yong-An Road, Xi-Cheng District, Beijing, 100050, China
| | - Minghua Zheng
- MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China
| | - Hao Ren
- Department of Radiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Zhenghan Yang
- Department of Radiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xiaojuan Ou
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, 95 Yong-An Road, Xi-Cheng District, Beijing, 100050, China
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, 95 Yong-An Road, Xi-Cheng District, Beijing, 100050, China
| | - Hong You
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, 95 Yong-An Road, Xi-Cheng District, Beijing, 100050, China.
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Wang Y, Wang M, Liu C, Hao M, Wang W, Li Y, Shi J, Jia X, Zhang X, Dang S. Global burden of liver cirrhosis 1990-2019 and 20 years forecast: results from the global burden of disease study 2019. Ann Med 2024; 56:2328521. [PMID: 38727511 PMCID: PMC11089929 DOI: 10.1080/07853890.2024.2328521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 02/01/2024] [Accepted: 03/04/2024] [Indexed: 05/15/2024] Open
Abstract
BACKGROUND Cirrhosis is a disease that imposes a heavy burden worldwide, but its incidence varies widely by region. Therefore, we analysed data on the incidence and mortality of cirrhosis in 204 countries and territories from 1990-2019 and projected the disease development from 2019-2039. METHODS Data on the incidence and mortality of liver cirrhosis from 1990 to 2019 were acquired from the public Global Burden of Disease (GBD) study. In addition, the average annual percentage change (AAPC) and estimated annual percentage change (EAPC) of the age-standardized rate (ASR) of cirrhosis in different regions were calculated. The estimates of risk factor exposure were summarized, and the proportion of causes and risk factors of liver cirrhosis and their relationship with the human development index (HDI) and socio-demographic index (SDI) were analysed. Trends in the incidence of cirrhosis in 2019-2039 were predicted using Nordpred and BAPC models. RESULTS Globally, the ASR of cirrhosis incidence decreased by 0.05% per year from 25.7/100,000 in 1990 to 25.3/100,000 in 2019. The mortality risk associated with cirrhosis is notably lower in females than in males (13 per 100,000 vs 25 per 100,000). The leading cause of cirrhosis shifted from hepatitis B to C. Globally, alcohol use increased by 14%. In line, alcohol use contributed to 49.3% of disability-adjusted life years (DALYs) and 48.4% of global deaths from liver cirrhosis. Countries with a low ASR in 1990 experienced a faster increase in cirrhosis, whereas in 2019, the opposite was observed. In countries with high SDI, the ASR of cirrhosis is generally lower. Finally, projections indicate that the number and incidence of cirrhosis will persistently rise from 2019-2039. CONCLUSIONS Cirrhosis poses an increasing health burden. Given the changing etiology, there is an imperative to strengthen the prevention of hepatitis C and alcohol consumption, to achieve early reduce the incidence of cirrhosis.
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Affiliation(s)
- Yikai Wang
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Muqi Wang
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Chenrui Liu
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Miao Hao
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Wenjun Wang
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Yaping Li
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Juanjuan Shi
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Xiaoli Jia
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Xin Zhang
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Shuangsuo Dang
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
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8
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Cen X, Wang W, Hong S, Wang Q, Wang N, Mo L, Li J, Li J. Integrated microbiome and metabolomic analyses revealed the antifibrotic effect of vanillic acid on thioacetamide-induced liver fibrosis in mice. Food Funct 2024; 15:11780-11794. [PMID: 39545308 DOI: 10.1039/d4fo02309a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2024]
Abstract
Vanillic acid (VA) is a natural phenolic acid compound that is widely found in various foods and medicinal plants, with a remarkable antifibrotic effect observed in animal studies, but its exact antifibrotic mechanism remains unclear. Herein, hepatic function, fibrotic index, and histopathological, microbiome, and metabolomic methods were used to investigate the potential mechanisms behind the improvement effect of vanillic acid against thioacetamide (TAA)-induced liver fibrosis in mice. Our results showed that VA reversed TAA-induced liver fibrosis manifested a decrease in collagen fiber deposition, serum transaminase, serum hepatic fibrotic index, and liver inflammation indicator levels. When analyzed, TAA injection mainly increased the abundance of Akkermansia and Roseburia and significantly reduced the abundance of Anaerotruncus. VA reversed these changes back to normal levels to varying degrees. Metabolomic profiling demonstrated that VA treatment was efficacious in modulating several key liver metabolites involved in neuroactive ligand-receptor interaction, prolactin signaling pathway, estrogen signaling pathway, and glutathione metabolism. Conclusively, VA may ameliorate liver damage and suppress the fibrogenesis caused by thioacetamide by correcting intestinal microbiota disorders and promoting normal hepatic metabolism. This research provides a novel perspective on vanillic acid as a dietary supplement for hepatic fibrosis improvement.
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Affiliation(s)
- Xiaofeng Cen
- Department of Nutrition and Food Hygiene, School of Public Health, Guilin Medical University, Guilin, China.
- Guangxi Health Commission Key Laboratory of Entire Lifecycle Health and Care, School of Public Health, Guilin Medical University, 541199, Guilin, China
- The Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, School of Public Health, Guilin Medical University, 541199, Guilin, China
| | - Wei Wang
- Department of Nutrition and Food Hygiene, School of Public Health, Guilin Medical University, Guilin, China.
- Guangxi Health Commission Key Laboratory of Entire Lifecycle Health and Care, School of Public Health, Guilin Medical University, 541199, Guilin, China
- The Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, School of Public Health, Guilin Medical University, 541199, Guilin, China
| | - Siyan Hong
- Department of Nutrition and Food Hygiene, School of Public Health, Guilin Medical University, Guilin, China.
- Guangxi Health Commission Key Laboratory of Entire Lifecycle Health and Care, School of Public Health, Guilin Medical University, 541199, Guilin, China
- The Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, School of Public Health, Guilin Medical University, 541199, Guilin, China
| | - Qin Wang
- Guangxi Health Commission Key Laboratory of Entire Lifecycle Health and Care, School of Public Health, Guilin Medical University, 541199, Guilin, China
- The Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, School of Public Health, Guilin Medical University, 541199, Guilin, China
| | - Na Wang
- Department of Nutrition and Food Hygiene, School of Public Health, Guilin Medical University, Guilin, China.
- Guangxi Health Commission Key Laboratory of Entire Lifecycle Health and Care, School of Public Health, Guilin Medical University, 541199, Guilin, China
- The Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, School of Public Health, Guilin Medical University, 541199, Guilin, China
| | - Ling Mo
- Department of Nutrition and Food Hygiene, School of Public Health, Guilin Medical University, Guilin, China.
- Guangxi Health Commission Key Laboratory of Entire Lifecycle Health and Care, School of Public Health, Guilin Medical University, 541199, Guilin, China
- The Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, School of Public Health, Guilin Medical University, 541199, Guilin, China
| | - Jingjing Li
- Department of Nutrition and Food Hygiene, School of Public Health, Guilin Medical University, Guilin, China.
- Guangxi Health Commission Key Laboratory of Entire Lifecycle Health and Care, School of Public Health, Guilin Medical University, 541199, Guilin, China
- The Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, School of Public Health, Guilin Medical University, 541199, Guilin, China
| | - Jingwen Li
- Department of Nutrition and Food Hygiene, School of Public Health, Guilin Medical University, Guilin, China.
- Guangxi Health Commission Key Laboratory of Entire Lifecycle Health and Care, School of Public Health, Guilin Medical University, 541199, Guilin, China
- The Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, School of Public Health, Guilin Medical University, 541199, Guilin, China
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9
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Li H, Ye J, Dong Y, Kong W, Qian G, Xie Y. U-shaped association of serum vitamin A concentrations with all-cause mortality in patients with NAFLD: results from the NHANES database prospective cohort study. Front Nutr 2024; 11:1467659. [PMID: 39539372 PMCID: PMC11558463 DOI: 10.3389/fnut.2024.1467659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Accepted: 10/14/2024] [Indexed: 11/16/2024] Open
Abstract
Background Previous studies have demonstrated a significant association between serum vitamin A concentration and non-alcoholic fatty liver disease (NAFLD) development. However, the long-term prognostic implications of serum vitamin A in patients with NAFLD remain underexplored. This study aims to investigate whether there exists a correlation between serum vitamin A concentrations and overall mortality among subjects diagnosed with NAFLD. Methods To investigate the association between serum vitamin A concentrations and NAFLD outcomes, we conducted prospective cohort studies using data from the 1999-2006 and 2017-2018 National Health and Nutrition Examination Survey (NHANES). We utilized a multivariate Cox regression model to explore the relationship between serum vitamin A levels and all-cause mortality. Survival curves related to serum vitamin A were constructed using the Kaplan-Meier method. Additionally, the restricted cubic splines (RCS) method was applied to examine potential nonlinear relationships between serum vitamin A concentrations and all-cause mortality of NAFLD. Results Over a median follow-up period of 10.3 years, a total of 1,399 all-cause deaths were recorded. The weighted average concentration of serum vitamin A was 61.48 ± 0.37 μg/dL. After adjusting for potential confounders, a significant U-shaped relationship was identified between serum vitamin A concentrations and the risk of all-cause mortality in NAFLD patients. This relationship was particularly pronounced in men and elderly individuals aged 60 to 85. Conclusion Our study reveals a significant non-linear relationship between serum vitamin A concentrations and the risk of all-cause mortality in patients with NAFLD. These findings underscore the importance of monitoring and maintaining optimal serum vitamin A levels to potentially improve survival outcomes in NAFLD patients.
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Affiliation(s)
- Hui Li
- Health Science Center, Ningbo University, Ningbo, Zhejiang, China
| | - Jiayuan Ye
- Department of Infectious Diseases, Shangyu People's Hospital of Shaoxing, Shaoxing, Zhejiang, China
| | - Yitian Dong
- Health Science Center, Ningbo University, Ningbo, Zhejiang, China
| | - Weiliang Kong
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Guoqing Qian
- Department of Infectious Diseases, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China
- Department of Hepatology, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Yilian Xie
- Department of Infectious Diseases, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China
- Department of Hepatology, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China
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10
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Papadimitriou K, Mousiolis AC, Mintziori G, Tarenidou C, Polyzos SA, Goulis DG. Hypogonadism and nonalcoholic fatty liver disease. Endocrine 2024; 86:28-47. [PMID: 38771482 DOI: 10.1007/s12020-024-03878-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Accepted: 05/12/2024] [Indexed: 05/22/2024]
Abstract
Nonalcoholic fatty liver disease (NAFLD), recently proposed to be renamed to metabolic dysfunction-associated steatotic liver disease (MASLD), is a major global public health concern, affecting approximately 25-30% of the adult population and possibly leading to cirrhosis, hepatocellular carcinoma, and liver transplantation. The liver is involved in the actions of sex steroids via their hepatic metabolism and production of the sex hormone-binding globulin (SHBG). Liver disease, including NAFLD, is associated with reproductive dysfunction in men and women, and the prevalence of NAFLD in patients with hypogonadism is considerable. A wide spectrum of possible pathophysiological mechanisms linking NAFLD and male/female hypogonadism has been investigated. As therapies targeting NAFLD may impact hypogonadism in men and women, and vice versa, treatments of the latter may affect NAFLD, and an insight into their pathophysiological pathways is imperative. This paper aims to elucidate the complex association between NAFLD and hypogonadism in men and women and discuss the therapeutic options and their impact on both conditions.
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Affiliation(s)
- Kasiani Papadimitriou
- Unit of Reproductive Endocrinology, First Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece.
| | - Athanasios C Mousiolis
- Unit of Reproductive Endocrinology, First Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Gesthimani Mintziori
- Unit of Reproductive Endocrinology, First Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | | | - Stergios A Polyzos
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Dimitrios G Goulis
- Unit of Reproductive Endocrinology, First Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
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11
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Tung HC, Kim JW, Zhu J, Li S, Yan J, Liu Q, Koo I, Koshkin SA, Hao F, Zhong G, Xu M, Wang Z, Wang J, Huang Y, Xi Y, Cai X, Xu P, Ren S, Higashiyama T, Gonzalez FJ, Li S, Isoherranen N, Yang D, Ma X, Patterson AD, Xie W. Inhibition of heme-thiolate monooxygenase CYP1B1 prevents hepatic stellate cell activation and liver fibrosis by accumulating trehalose. Sci Transl Med 2024; 16:eadk8446. [PMID: 39321267 DOI: 10.1126/scitranslmed.adk8446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 04/05/2024] [Accepted: 09/04/2024] [Indexed: 09/27/2024]
Abstract
Activation of extracellular matrix-producing hepatic stellate cells (HSCs) is a key event in liver fibrogenesis. We showed that the expression of the heme-thiolate monooxygenase cytochrome P450 1B1 (CYP1B1) was elevated in human and mouse fibrotic livers and activated HSCs. Systemic or HSC-specific ablation and pharmacological inhibition of CYP1B1 attenuated HSC activation and protected male but not female mice from thioacetamide (TAA)-, carbon tetrachloride (CCl4)-, or bile duct ligation (BDL)-induced liver fibrosis. Metabolomic analysis revealed an increase in the disaccharide trehalose in CYP1B1-deficient HSCs resulting from intestinal suppression of the trehalose-metabolizing enzyme trehalase, whose gene we found to be a target of RARα. Trehalose or its hydrolysis-resistant derivative lactotrehalose exhibited potent antifibrotic activity in vitro and in vivo by functioning as an HSC-specific autophagy inhibitor, which may account for the antifibrotic effect of CYP1B1 inhibition. Our study thus reveals an endobiotic function of CYP1B1 in liver fibrosis in males, mediated by liver-intestine cross-talk and trehalose. At the translational level, pharmacological inhibition of CYP1B1 or the use of trehalose/lactotrehalose may represent therapeutic strategies for liver fibrosis.
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Affiliation(s)
- Hung-Chun Tung
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Jong-Won Kim
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Junjie Zhu
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Sihan Li
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Jiong Yan
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Qing Liu
- Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802, USA
| | - Imhoi Koo
- Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802, USA
| | - Sergei A Koshkin
- Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802, USA
| | - Fuhua Hao
- Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802, USA
| | - Guo Zhong
- Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA 98195, USA
| | - Meishu Xu
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Zehua Wang
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Jingyuan Wang
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Yixian Huang
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Yue Xi
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Xinran Cai
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Pengfei Xu
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Songrong Ren
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | | | - Frank J Gonzalez
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Song Li
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Nina Isoherranen
- Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA 98195, USA
| | - Da Yang
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Xiaochao Ma
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Andrew D Patterson
- Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802, USA
| | - Wen Xie
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA
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12
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Fu CE, Teng M, Tung D, Ramadoss V, Ong C, Koh B, Lim WH, Tan DJH, Koh JH, Nah B, Syn N, Tamaki N, Siddiqui MS, Wijarnpreecha K, Ioannou GN, Nakajima A, Noureddin M, Sanyal AJ, Ng CH, Muthiah M. Sex and Race-Ethnic Disparities in Metabolic Dysfunction-Associated Steatotic Liver Disease: An Analysis of 40,166 Individuals. Dig Dis Sci 2024; 69:3195-3205. [PMID: 38940975 DOI: 10.1007/s10620-024-08540-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 06/20/2024] [Indexed: 06/29/2024]
Abstract
BACKGROUND To overcome the limitations of the term "non-alcoholic fatty liver disease" (NAFLD), the term metabolic-associated steatotic liver disease (MASLD) was introduced. While epidemiologic studies have been conducted on MASLD, there is limited evidence on its associated sex and ethnic variations. AIMS This study assesses the differences across sex and race-ethnicity on the prevalence, associated risk factors and adverse outcomes in individuals with MASLD. METHODS Data retrieved from the National Health and Nutrition Examination Survey between 1999 to 2018 was analyzed. Prevalence, clinical characteristics, and outcomes were evaluated according to sex and race-ethnicity. Adverse outcomes and mortality events were analyzed using multivariate analyses. RESULTS Of 40,166 individuals included, 37.63% had MASLD. There was a significant increase in MASLD prevalence from 1999 to 2018 among Mexican Americans (Annual Percentage Change [APC] + 1.889%, p < 0.001), other Hispanics (APC + 1.661%, p = 0.013), NH Whites (APC + 1.084%, p = 0.018), NH Blacks (APC + 1.108%, p = 0.007), and females (APC + 0.879%, p = 0.030), but not males. Females with MASLD were at lower risk of all-cause (HR: 0.766, 95%CI 0.711 to 0.825, p < 0.001), cardiovascular disease-related (CVD) (SHR: 0.802, 95% CI 0.698 to 0.922, p = 0.002) and cancer-related mortality (SHR: 0.760, 95% CI 0.662 to 0.873, p < 0.001). Significantly, NH Blacks have the highest risk of all-cause and CVD-related mortality followed by NH Whites then Mexican Americans. CONCLUSION There has been an increase in prevalence in most race-ethnicities over time. While the change in definition shows no significant differences in previous associations found in NAFLD, the increased mortality in NH Whites relative to Mexican Americans remains to be explored.
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Affiliation(s)
- Clarissa Elysia Fu
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 10 Medical Dr, Singapore, 117597, Singapore
| | - Margaret Teng
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
| | - Daniel Tung
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
| | - Vijay Ramadoss
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Christen Ong
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 10 Medical Dr, Singapore, 117597, Singapore
| | - Benjamin Koh
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 10 Medical Dr, Singapore, 117597, Singapore
| | - Wen Hui Lim
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 10 Medical Dr, Singapore, 117597, Singapore
| | - Darren Jun Hao Tan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 10 Medical Dr, Singapore, 117597, Singapore
| | - Jia Hong Koh
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 10 Medical Dr, Singapore, 117597, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
| | - Benjamin Nah
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
| | - Nicholas Syn
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 10 Medical Dr, Singapore, 117597, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- National University Centre for Organ Transplantation, National University Health System, Singapore, Singapore
| | - Nobuharu Tamaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Mohammad Shadab Siddiqui
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Karn Wijarnpreecha
- Division of Gastroenterology and Hepatology, University of Arizona College of Medicine Phoenix, Phoenix, AZ, USA
| | - George N Ioannou
- Division of Gastroenterology, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, WA, USA
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Kanagawa, Japan
| | - Mazen Noureddin
- Houston Research Institute, Houston Methodist Hospital, Houston, USA
| | - Arun J Sanyal
- Department of Internal Medicine, Stravitz-Sanyal Institute of Liver Disease and Metabolic Health,, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Cheng Han Ng
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 10 Medical Dr, Singapore, 117597, Singapore.
- Ministry of Health Holdings, Singapore, Singapore.
- Department of Medicine, Kurume University School of Medicine, Kurume, Japan.
| | - Mark Muthiah
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 10 Medical Dr, Singapore, 117597, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
- National University Centre for Organ Transplantation, National University Health System, Singapore, Singapore
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Gao H, Peng X, Li N, Gou L, Xu T, Wang Y, Qin J, Liang H, Ma P, Li S, Wu J, Qin X, Xue B. Emerging role of liver-bone axis in osteoporosis. J Orthop Translat 2024; 48:217-231. [PMID: 39290849 PMCID: PMC11407911 DOI: 10.1016/j.jot.2024.07.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 06/19/2024] [Accepted: 07/16/2024] [Indexed: 09/19/2024] Open
Abstract
Background Increasing attention to liver-bone crosstalk has spurred interest in targeted interventions for various forms of osteoporosis. Liver injury induced by different liver diseases can cause an imbalance in bone metabolism, indicating a novel regulatory paradigm between the liver and bone. However, the role of the liver-bone axis in both primary and secondary osteoporosis remains inadequately elucidated. Therefore, exploring the exact regulatory mechanisms of the liver-bone axis may offer innovative clinical approaches for treating diseases associated with the liver and bone. Methods Here, we summarize the latest research on the liver-bone axis by searching the PubMed and Web of Science databases and discuss the possible mechanism of the liver-bone axis in different types of osteoporosis. The literature directly reporting the regulatory role of the liver-bone axis in different types of osteoporosis from the PubMed and Web of Science databases has been included in the discussion of this review (including but not limited to the definition of the liver-bone axis, clinical studies, and basic research). In addition, articles discussing changes in bone metabolism caused by different etiologies of liver injury have also been included in the discussion of this review (including but not limited to clinical studies and basic research). Results Several endocrine factors (IGF-1, FGF21, hepcidin, vitamin D, osteocalcin, OPN, LCAT, Fetuin-A, PGs, BMP2/9, IL-1/6/17, and TNF-α) and key genes (SIRT2, ABCB4, ALDH2, TFR2, SPTBN1, ZNF687 and SREBP2) might be involved in the regulation of the liver-bone axis. In addition to the classic metabolic pathways involved in inflammation and oxidative stress, iron metabolism, cholesterol metabolism, lipid metabolism and immunometabolism mediated by the liver-bone axis require more research to elucidate the regulatory mechanisms involved in osteoporosis. Conclusion During primary and secondary osteoporosis, the liver-bone axis is responsible for liver and bone homeostasis via several hepatokines and osteokines as well as biochemical signaling. Combining multiomics technology and data mining technology could further advance our understanding of the liver-bone axis, providing new clinical strategies for managing liver and bone-related diseases.The translational potential of this article is as follows: Abnormal metabolism in the liver could seriously affect the metabolic imbalance of bone. This review summarizes the indispensable role of several endocrine factors and biochemical signaling pathways involved in the liver-bone axis and emphasizes the important role of liver metabolic homeostasis in the pathogenesis of osteoporosis, which provides novel potential directions for the prevention, diagnosis, and treatment of liver and bone-related diseases.
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Affiliation(s)
- Hongliang Gao
- Department of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu, PR China
- Jiangsu Key Laboratory of Early Development and Chronic Disease Prevention in Children,Nanjing, Jiangsu,PR China
- Core Laboratory, Department of Clinical Laboratory, Sir Run Run Hospital, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, PR China
- Department of pathophysiology, Wannan Medical College, Wuhu, Anhui, PR China
| | - Xing Peng
- Core Laboratory, Department of Clinical Laboratory, Sir Run Run Hospital, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, PR China
| | - Ning Li
- Core Laboratory, Department of Clinical Laboratory, Sir Run Run Hospital, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, PR China
| | - Liming Gou
- Department of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu, PR China
- Jiangsu Key Laboratory of Early Development and Chronic Disease Prevention in Children,Nanjing, Jiangsu,PR China
| | - Tao Xu
- Core Laboratory, Department of Clinical Laboratory, Sir Run Run Hospital, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, PR China
| | - Yuqi Wang
- Core Laboratory, Department of Clinical Laboratory, Sir Run Run Hospital, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, PR China
| | - Jian Qin
- Department of Orthoprdics, Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu , PR China
| | - Hui Liang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, PR China
| | - Peiqi Ma
- Medical Imaging Center, Fuyang People's Hospital, Fuyang, Anhui, PR China
| | - Shu Li
- Department of pathophysiology, Wannan Medical College, Wuhu, Anhui, PR China
| | - Jing Wu
- Department of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu, PR China
- Jiangsu Key Laboratory of Early Development and Chronic Disease Prevention in Children,Nanjing, Jiangsu,PR China
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, Jiangsu, PR China
| | - Xihu Qin
- Department of General Surgery, The Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Changzhou, Jiangsu, PR China
| | - Bin Xue
- Department of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu, PR China
- Jiangsu Key Laboratory of Early Development and Chronic Disease Prevention in Children,Nanjing, Jiangsu,PR China
- Core Laboratory, Department of Clinical Laboratory, Sir Run Run Hospital, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, PR China
- Department of General Surgery, The Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Changzhou, Jiangsu, PR China
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Zhang X, Liu M, Wang Z, Wang P, Kong L, Wu J, Wu W, Ma L, Jiang S, Ren W, Du L, Ma W, Liu X. A review of the botany, phytochemistry, pharmacology, synthetic biology and comprehensive utilization of Silybum marianum. Front Pharmacol 2024; 15:1417655. [PMID: 39055491 PMCID: PMC11269164 DOI: 10.3389/fphar.2024.1417655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 06/20/2024] [Indexed: 07/27/2024] Open
Abstract
Silybum marianum (L.) Gaertn, a herbaceous plant with a long history in traditional medicine for the treatment of hepatobiliary diseases, particularly in Europe, which has attracted attention for its remarkable therapeutic effect. This review systematically summarizes the research progress in the botany, phytochemistry, pharmacology, comprehensive utilization and synthetic biology of S. marianum. Up to now, more than 20 types of flavonolignan components have been isolated from S. marianum. In addition, the rearch on fatty acids and triterpenoids is also constantly improving. Among them, silybin is the most active compound in flavonolignans components. Its pharmacological effects in vivo and in vitro include anti-inflammatory, antioxidant, anti-tumour, hypoglycaemic, neuroprotective and immunoregulatory properties. The use of coniferyl alcohol and taxifolin as substrates to produce silybin and isosilybin under the action of enzyme catalysis is the commonly used biosynthetic pathway of silymarin, which provides support for a comprehensive analysis of the synthetic pathway of silymarin. In addition to medicinal use, the extracts of plants also have broad application prospects in the production of food, healthcare products, cosmetics and other aspects. In addition, the chemical composition, pharmacological mechanism and synthetic biology of S. marianum need to be further studied, which is very important for its clinical efficacy and resource development.
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Affiliation(s)
- Xiaozhuang Zhang
- College of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Meiqi Liu
- College of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Zhen Wang
- College of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Panpan Wang
- College of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Lingyang Kong
- College of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Jianhao Wu
- College of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Wei Wu
- College of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Lengleng Ma
- College of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Shan Jiang
- College of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Weichao Ren
- College of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Likun Du
- First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Wei Ma
- College of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Xiubo Liu
- College of Jiamusi, Heilongjiang University of Chinese Medicine, Jiamusi, China
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15
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Toniutto P, Shalaby S, Mameli L, Morisco F, Gambato M, Cossiga V, Guarino M, Marra F, Brunetto MR, Burra P, Villa E. Role of sex in liver tumor occurrence and clinical outcomes: A comprehensive review. Hepatology 2024; 79:1141-1157. [PMID: 37013373 DOI: 10.1097/hep.0000000000000277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Accepted: 12/06/2022] [Indexed: 04/05/2023]
Abstract
Clinical research on sex-based differences in the manifestations, pathophysiology, and prevalence of several diseases, including those affecting the liver, has expanded considerably in recent years. Increasing evidence suggests that liver diseases develop, progress, and respond to treatment differently depending on the sex. These observations support the concept that the liver is a sexually dimorphic organ in which estrogen and androgen receptors are present, which results in disparities between men and women in liver gene expression patterns, immune responses, and the progression of liver damage, including the propensity to develop liver malignancies. Sex hormones play protective or deleterious roles depending on the patient's sex, the severity of the underlying disease, and the nature of precipitating factors. Moreover, obesity, alcohol consumption, and active smoking, as well as social determinants of liver diseases leading to sex-related inequalities, may interact strongly with hormone-related mechanisms of liver damage. Drug-induced liver injury, viral hepatitis, and metabolic liver diseases are influenced by the status of sex hormones. Available data on the roles of sex hormones and gender differences in liver tumor occurrence and clinical outcomes are conflicting. Here, we critically review the main gender-based differences in the molecular mechanisms associated with liver carcinogenesis and the prevalence, prognosis, and treatment of primary and metastatic liver tumors.
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Affiliation(s)
- Pierluigi Toniutto
- Hepatology and Liver Transplantation Unit, Azienda Sanitaria Universitaria Integrata, Department of Medical Area, University of Udine, Udine, Italy
| | - Sarah Shalaby
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Laura Mameli
- Liver and Pancreas Transplant Center, Azienda Ospedaliera Brotzu Piazzale Ricchi 1, Cagliari, Italy
| | - Filomena Morisco
- Department of Clinical Medicine and Surgery, Departmental Program "Diseases of the Liver and Biliary System," University of Naples "Federico II," Napoli, Italy
| | - Martina Gambato
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Valentina Cossiga
- Department of Clinical Medicine and Surgery, Departmental Program "Diseases of the Liver and Biliary System," University of Naples "Federico II," Napoli, Italy
| | - Maria Guarino
- Department of Clinical Medicine and Surgery, Departmental Program "Diseases of the Liver and Biliary System," University of Naples "Federico II," Napoli, Italy
| | - Fabio Marra
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | | | - Patrizia Burra
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Erica Villa
- Gastroenterology Department, University of Modena and Reggio Emilia, Modena, Italy
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Joo SK, Kim W. Sex/Gender Differences in Liver Diseases. SEX/GENDER-SPECIFIC MEDICINE IN CLINICAL AREAS 2024:209-217. [DOI: 10.1007/978-981-97-0130-8_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Liu ZP, Ouyang GQ, Huang GZ, Wei J, Dai L, He SQ, Yuan GD. Global burden of cirrhosis and other chronic liver diseases due to nonalcoholic fatty liver disease, 1990-2019. World J Hepatol 2023; 15:1210-1225. [PMID: 38075011 PMCID: PMC10698345 DOI: 10.4254/wjh.v15.i11.1210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 08/29/2023] [Accepted: 10/30/2023] [Indexed: 11/24/2023] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) has become the leading cause of cirrhosis and other chronic liver diseases (COCLDs). AIM To conduct a comprehensive and comparable updated analysis of the global, regional, and national burden of COCLDs due to NAFLD in 204 countries and territories from 1990 and 2019 by age, sex, and sociodemographic index. METHODS Data on COCLDs due to NAFLD were collected from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019. Numbers and age-standardized prevalence, death, and disability-adjusted life years (DALYs) were estimated through a systematic analysis of modelled data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019. The estimated annual percentage change was used to determine the burden trend. RESULTS In 2019, the global age-standardized prevalence rate of COCLDs due to NAFLD was 15022.90 per 100000 population [95% uncertainty interval (UI): 13493.19-16764.24], which increased by 24.51% (22.63% to 26.08%) from 1990, with an estimated annual percentage change of 0.78 (95% confidence interval: 0.74-0.82). In the same year, however, the age-standardized death rate and age-standardized DALYs per 100000 population were 1.66 (95%UI: 1.20-2.17) and 43.69 (95%UI: 31.28-58.38), respectively. North Africa and the Middle East had the highest prevalence rates of COCLDs due to NAFLD. The death rate increased with age up to the 95+ age group for both sexes. Males had higher numbers of prevalence, death rate, and DALYs than females across all age groups before the 65-69 age group. The sociodemographic index was negatively correlated with the age-standardized DALYs. CONCLUSION Globally, the age-standardized prevalence rate has increased during the past three decades. However, the age-standardized death rate and age-standardized DALYs decreased. There is geographical variation in the burden of COCLDs due to NAFLD. It is strongly recommended to improve the data quality of COCLDs due to NAFLD across all countries and regions to facilitate better monitoring of the burden of COCLDs due to NAFLD.
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Affiliation(s)
- Zhi-Peng Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Guo-Qing Ouyang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Guo-Zhen Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Jie Wei
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Luo Dai
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Song-Qing He
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China.
| | - Guan-Dou Yuan
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
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18
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Zhu N, Song Y, Zhang C, Wang K, Han J. Association between the peripheral neutrophil-to-lymphocyte ratio and metabolic dysfunction-associated steatotic liver disease in patients with type 2 diabetes. Front Med (Lausanne) 2023; 10:1294425. [PMID: 38020132 PMCID: PMC10657835 DOI: 10.3389/fmed.2023.1294425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Accepted: 10/25/2023] [Indexed: 12/01/2023] Open
Abstract
Background Metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes frequently co-occur, imposing a tremendous medical burden. A convenient and effective MASLD indicator will be beneficial to the early diagnosis of disease. In the clinical laboratory, the neutrophil-to-lymphocyte ratio (NLR) is a readily accessible hematological marker. This study designed to determine the relation between the NLR and MASLD in type 2 diabetes patients. Methods Data from 1,151 type 2 diabetes inpatients without infections, malignancy or hematological diseases who were recruited from 2016 through 2022 were analyzed in the retrospective study. The patients were stratified into NLR tertiles (total population: high NLR level > 2.18; middle NLR level: 1.58-2.18; low NLR level < 1.58), with additional subgroup stratification by sex (men: high NLR level > 2.21; middle NLR level: 1.60-2.21; and low NLR level < 1.60; women: high NLR level > 2.12; middle NLR level: 1.53-2.12; and low NLR level < 1.53). After adjusting for confounders (age, sex, weight, Glu, ALT and TG) associated with MASLD, the odds ratio (OR) and the corresponding 95% confidence interval (CI) of the NLR were obtained by using a binary logistic regression analysis to verify the correlation between the NLR and MASLD. Results Compared to non-MASLD patients, MASLD patients had higher weight, blood glucose, insulin and C-peptide, worse liver function (higher ALT and GGT), lower HDL (all p < 0.05), and lower NLR (p < 0.001). The prevalence of MASLD was 43.75% (high NLR level), 55.21% (middle NLR level) and 52.22% (low NLR level) (p < 0.05). Compared to those of the high NLR level, the adjusted ORs and 95% CIs of the middle and low NLR levels were 1.624 (95% CI: 1.141-2.311) and 1.456 (95% CI: 1.025-2.068), for all subjects, while they were 1.640 (95% CI: 1.000-2.689) and 1.685 (95% CI: 1.026-2.766), for men. Conclusion A low NLR is associated with a greater risk of MASLD.
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Affiliation(s)
- Nan Zhu
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China
| | - Yongfeng Song
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Chen Zhang
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China
| | - Kai Wang
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Junming Han
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China
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Cooper KM, Delk M, Devuni D, Sarkar M. Sex differences in chronic liver disease and benign liver lesions. JHEP Rep 2023; 5:100870. [PMID: 37791378 PMCID: PMC10542645 DOI: 10.1016/j.jhepr.2023.100870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 06/23/2023] [Accepted: 07/01/2023] [Indexed: 10/05/2023] Open
Abstract
The epidemiology, natural history, and therapeutic responses of chronic liver diseases and liver lesions often vary by sex. In this review, we summarize available clinical and translational data on these aspects of the most common liver conditions encountered in clinical practice, including the potential contributions of sex hormones to the underlying pathophysiology of observed differences. We also highlight areas of notable knowledge gaps and discuss sex disparities in access to liver transplant and potential strategies to address these barriers. Given established sex differences in immune response, drug metabolism, and response to liver-related therapies, emerging clinical trials and epidemiological studies should prioritize dedicated analyses by sex to inform sex-specific approaches to liver-related care.
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Affiliation(s)
- Katherine M. Cooper
- UMass Chan Medical School, Department of Medicine, Division of Gastroenterology/Hepatology, Worcester, MA, United States
| | - Molly Delk
- University of California San Francisco, Department of Medicine, Division of Gastroenterology/Hepatology, San Francisco, CA, United States
| | - Deepika Devuni
- UMass Chan Medical School, Department of Medicine, Division of Gastroenterology/Hepatology, Worcester, MA, United States
| | - Monika Sarkar
- University of California San Francisco, Department of Medicine, Division of Gastroenterology/Hepatology, San Francisco, CA, United States
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20
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Tan D, Chan KE, Wong ZY, Ng CH, Xiao J, Lim WH, Tay P, Tang A, Fu CE, Muthiah M, Nah B, Tan EX, Teng ML, Siddiqui MS, Dan YY, Lim SG, Loomba R, Huang DQ. Global Epidemiology of Cirrhosis: Changing Etiological Basis and Comparable Burden of Nonalcoholic Steatohepatitis between Males and Females. Dig Dis 2023; 41:900-912. [PMID: 37703863 PMCID: PMC10716870 DOI: 10.1159/000533946] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 08/09/2023] [Indexed: 09/15/2023]
Abstract
INTRODUCTION The etiology of liver diseases has changed significantly, but its impact on the comparative burden of cirrhosis between males and females is unclear. We estimated sex differences in the burden of cirrhosis across 204 countries and territories from 2010 to 2019. METHODS We analyzed temporal trends in the burden of cirrhosis using the methodology framework of the 2019 Global Burden of Disease study. We estimated annual frequencies and age-standardized rates (ASRs) of cirrhosis incidence, death, and disability-adjusted life-years (DALYs) by sex, region, country, and etiology. RESULTS In 2019, the frequency of incident cases, deaths, and DALYs due to cirrhosis was 1,206,125, 969,068, and 31,781,079 in males versus 845,429, 502,944, and 14,408,336 in females, respectively. From 2010 to 2019, the frequency of cirrhosis deaths increased by 9% in males and 12% in females. Incidence ASRs remained stable in males but increased in females, while death ASRs declined in both. Death ASRs for both sexes declined in all regions, except in the Americas where they remained stable. In 2019, alcohol was the leading cause of cirrhosis deaths in males, and hepatitis C in females. Death ASRs declined for all etiologies in both sexes, except in nonalcoholic steatohepatitis (NASH). The ratio of female-to-male incidence ASRs in 2019 was lowest in alcohol(0.5), and highest in NASH(1.3), while the ratio of female-to-male death ASRs was lowest in alcohol(0.3) and highest in NASH(0.8). CONCLUSION The global burden of cirrhosis is higher in males. However, incidence and death ASRs from NASH cirrhosis in females are comparable to that of males.
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Affiliation(s)
- Darren Tan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Kai En Chan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Zhen Yu Wong
- Nottingham Hospitals University Trust, Nottingham, UK
| | - Cheng Han Ng
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Jieling Xiao
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Wen Hui Lim
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Phoebe Tay
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Ansel Tang
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Clarissa Elysia Fu
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Mark Muthiah
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, Singapore
| | - Benjamin Nah
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Nottingham Hospitals University Trust, Nottingham, UK
| | - Eunice X. Tan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, Singapore
| | - Margaret L.P. Teng
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, Singapore
| | - Mohammad Shadab Siddiqui
- Division of Gastroenterology, Department of Internal Medicine, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, VA, USA
| | - Yock Young Dan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, Singapore
| | - Seng Gee Lim
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, Singapore
| | - Rohit Loomba
- Division of Gastroenterology, NAFLD Research Center, University of California at San Diego, La Jolla, CA, USA
- Division of Epidemiology, Department of Family Medicine and Public Health, University of California at San Diego, San Diego, CA, USA
| | - Daniel Q. Huang
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, Singapore
- Division of Gastroenterology, NAFLD Research Center, University of California at San Diego, La Jolla, CA, USA
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21
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Rose PC, Cotton MF, Otwombe K, Innes S, Nel ED. Liver transient elastography values in healthy South African children. BMC Pediatr 2023; 23:355. [PMID: 37443011 PMCID: PMC10339605 DOI: 10.1186/s12887-023-04170-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 06/30/2023] [Indexed: 07/15/2023] Open
Abstract
BACKGROUND Transient elastography (TE) is a rapid noninvasive ultrasound-based technology that measures liver stiffness as a surrogate for liver fibrosis and controlled attenuation parameter (CAP) as a measure of liver steatosis. However, normal ranges in children are not well defined in all populations. The aim of this study was to determine transient elastography values in healthy South African children. METHODS From April 2019 to December 2021, children were recruited from the HIV negative control group of a cohort study. Only children neither overweight nor obese, without evidence of liver disease, no medical condition or medication associated with hepatic steatosis or fibrosis and normal metabolic profile were included in this cross-sectional analysis. Clinical data, anthropometry and blood samples were collected on the same day as transient elastography with controlled attenuation parameter was performed. RESULTS 104 children (median age 12.8 years [IQR 11.4-14.8, range 7.9-17.7 years]; 59 [57%] boys) were included. Liver stiffness was positively correlated with age (Pearson's r = 0.39, p < 0.001). Median liver stiffness in boys (5.2 kPa [5th to 95th percentiles 3.6 to 6.8 kPa]) was greater than in girls (4.6 kPa [5th to 95th percentiles 3.6 to 6.1 kPa; p = 0.004]), but there was no difference by ethnicity. Median CAP was 179dB/m (5th to 95th percentiles 158 to 233dB/m). There was a positive correlation between CAP and body mass index (BMI) z-score, but no difference by age, sex, ethnicity or pubertal status. CONCLUSION Liver stiffness values increase with age and are higher in healthy South African boys than girls, whereas CAP values vary with BMI, but not with age or sex.
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Affiliation(s)
- Penelope C Rose
- Department of Paediatrics and Child Health, Tygerberg Hospital and Stellenbosch University, PO Box 241, Cape Town, 8000, South Africa.
| | - Mark F Cotton
- Department of Paediatrics and Child Health, Tygerberg Hospital and Stellenbosch University, PO Box 241, Cape Town, 8000, South Africa
- Family Center for Research with Ubuntu (FAMCRU), Cape Town, South Africa
| | - Kennedy Otwombe
- Perinatal HIV Research Unit, School of Public Health, Chris Hani Baragwanath Academic Hospital, University of the Witwatersrand, Johannesburg, South Africa
| | - Steve Innes
- Department of Paediatrics and Child Health, Tygerberg Hospital and Stellenbosch University, PO Box 241, Cape Town, 8000, South Africa
- Family Center for Research with Ubuntu (FAMCRU), Cape Town, South Africa
- Desmond Tutu HIV Centre, University of Cape Town, Cape Town, South Africa
| | - Etienne D Nel
- Department of Paediatrics and Child Health, Tygerberg Hospital and Stellenbosch University, PO Box 241, Cape Town, 8000, South Africa
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22
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Amini-Salehi E, Hassanipour S, Joukar F, Daryagasht AA, Khosousi MJ, Sadat Aleali M, Ansar MM, Heidarzad F, Abdzadeh E, Vakilpour A, Mansour-Ghanaei F. Risk Factors of Non-alcoholic Fatty Liver Disease in the Iranian Adult Population: A Systematic Review and Meta-analysis. HEPATITIS MONTHLY 2023; 23. [DOI: 10.5812/hepatmon-131523] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 01/07/2023] [Accepted: 01/18/2023] [Indexed: 01/03/2025]
Abstract
Context: Non-alcoholic fatty liver disease (NAFLD) is progressing considerably worldwide. Identifying the risk factors of NAFLD is a critical step in preventing its progression. Methods: In November 2022, two independent researchers studied seven databases, including PubMed, ISI/WoS, ProQuest, Scopus, SID, Magiran, and Google Scholar, and reference list of relevant articles, searching studies that assessed NAFLD risk factors in the Iranian adult population. Heterogeneity between studies was assessed by Cochran’s test and its composition using I2 statistics. A random-effects model was used when heterogeneity was observed; otherwise, a fixed-effects model was applied. Egger’s regression test and Trim-and-Fill analysis were used to assess publication bias. Comprehensive Meta-analysis software (version 3) was used for the analyses of the present study. Results: The results of this study showed significant associations between NAFLD with age (n = 15, odds ratio (OR) = 2.12, 95% CI: 1.79 - 2.51), body mass index (n = 46, OR = 5.00, 95% CI: 3.34 - 7.49), waist circumference (n = 20, OR = 6.37, 95% CI: 3.25 - 12.48), waist-to-hip ratio (n = 17, OR = 4.72, 95% CI: 3.93 - 5.66), total cholesterol (n = 39, OR = 1.80, 95% CI: 1.52 - 2.13), high-density lipoprotein (n = 37, OR = 0.53, 95% CI: 0.44 - 0.65), low-density lipoprotein (n = 31, OR = 1.68, 95% CI: 1.38 - 2.05), triglyceride (n = 31, OR = 3.21, 95% CI: 2.67 - 3.87), alanine aminotransferase (n = 26, OR = 4.06, 95% CI: 2.94 - 5.62), aspartate aminotransferase (n = 27, OR = 2.16, 95% CI: 1.50 - 3.12), hypertension (n = 13, OR = 2.53, 95% CI: 2.32 - 2.77), systolic blood pressure (n = 13, OR = 1.83, 95% CI: 1.53 - 2.18), diastolic blood pressure (n = 14, OR = 1.80, 95% CI: 1.48 - 2.20), fasting blood sugar (n = 31, OR = 2.91, 95% CI: 2.11- 4.01), homeostatic model assessment for insulin resistance (n = 5, OR = 1.92, 95% CI: 1.48 - 2.59), diabetes mellitus (n = 15, OR = 3.04, 95% CI: 2.46 - 3.75), metabolic syndrome (n = 10, OR = 3.56, 95% CI: 2.79 - 4.55), and physical activity (n = 11, OR = 0.32, 95% CI: 0.24 - 0.43) (P < 0.05). Conclusions: In conclusion, several factors are significantly associated with NAFLD. However, anthropometric indices had the strongest relationship with NAFLD in the Iranian adult population.
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23
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Ali Mondal S, Sathiaseelan R, Mann SN, Kamal M, Luo W, Saccon TD, Isola JVV, Peelor FF, Li T, Freeman WM, Miller BF, Stout MB. 17α-estradiol, a lifespan-extending compound, attenuates liver fibrosis by modulating collagen turnover rates in male mice. Am J Physiol Endocrinol Metab 2023; 324:E120-E134. [PMID: 36516471 PMCID: PMC9902223 DOI: 10.1152/ajpendo.00256.2022] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 12/13/2022] [Accepted: 12/13/2022] [Indexed: 12/15/2022]
Abstract
Estrogen signaling is protective against chronic liver diseases, although men and a subset of women are contraindicated for chronic treatment with 17β-estradiol (17β-E2) or combination hormone replacement therapies. We sought to determine if 17α-estradiol (17α-E2), a naturally occurring diastereomer of 17β-E2, could attenuate liver fibrosis. We evaluated the effects of 17α-E2 treatment on collagen synthesis and degradation rates using tracer-based labeling approaches in male mice subjected to carbon tetrachloride (CCl4)-induced liver fibrosis. We also assessed the effects of 17α-E2 on markers of hepatic stellate cell (HSC) activation, collagen cross-linking, collagen degradation, and liver macrophage content and polarity. We found that 17α-E2 significantly reduced collagen synthesis rates and increased collagen degradation rates, which was mirrored by declines in transforming growth factor β1 (TGF-β1) and lysyl oxidase-like 2 (LOXL2) protein content in liver. These improvements were associated with increased matrix metalloproteinase 2 (MMP2) activity and suppressed stearoyl-coenzyme A desaturase 1 (SCD1) protein levels, the latter of which has been linked to the resolution of liver fibrosis. We also found that 17α-E2 increased liver fetuin-A protein, a strong inhibitor of TGF-β1 signaling, and reduced proinflammatory macrophage activation and cytokines expression in the liver. We conclude that 17α-E2 reduces fibrotic burden by suppressing HSC activation and enhancing collagen degradation mechanisms. Future studies will be needed to determine if 17α-E2 acts directly in hepatocytes, HSCs, and/or immune cells to elicit these benefits.
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Affiliation(s)
- Samim Ali Mondal
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma
| | - Roshini Sathiaseelan
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma
- Department of Nutritional Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Shivani N Mann
- Department of Neuroscience, University of Arizona, Tucson, Arizona
| | - Maria Kamal
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Wenyi Luo
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Tatiana D Saccon
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma
| | - José V V Isola
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma
| | - Frederick F Peelor
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma
| | - Tiangang Li
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Willard M Freeman
- Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma
- Oklahoma City Veterans Affairs Medical Center, Oklahoma City, Oklahoma
| | - Benjamin F Miller
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma
- Oklahoma City Veterans Affairs Medical Center, Oklahoma City, Oklahoma
| | - Michael B Stout
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma
- Oklahoma City Veterans Affairs Medical Center, Oklahoma City, Oklahoma
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24
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Zhao M, Ma L, Honda T, Kato A, Ohshiro T, Yokoyama S, Yamamoto K, Ito T, Imai N, Ishizu Y, Nakamura M, Kawashima H, Tsuji NM, Ishigami M, Fujishiro M. Astaxanthin Attenuates Nonalcoholic Steatohepatitis with Downregulation of Osteoprotegerin in Ovariectomized Mice Fed Choline-Deficient High-Fat Diet. Dig Dis Sci 2023; 68:155-163. [PMID: 35397697 DOI: 10.1007/s10620-022-07489-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 03/14/2022] [Indexed: 02/01/2023]
Abstract
BACKGROUND Postmenopausal estrogen decline increases the risk of developing nonalcoholic steatohepatitis (NASH), and it might accelerate progression to cirrhosis and hepatocellular carcinoma. AIMS This study aimed to investigate a novel therapy for postmenopausal women who are diagnosed with NASH. METHODS Seven-week-old female C57BL/6 J mice were divided into three experimental groups as follows: (1) sham operation (SHAM group), (2) ovariectomy (OVX group), and (3) ovariectomy + 0.02% astaxanthin (OVX + ASTX group). These three groups of mice were fed a choline-deficient high-fat (CDHF) diet for 8 weeks. Blood serum and liver tissues were collected to examine liver injury, histological changes, and hepatic genes associated with NASH. An in vitro study was performed with the hepatic stellate cell line LX-2. RESULTS The administration of ASTX significantly improved pathological NASH with suppressed steatosis, inflammation, and fibrosis, in comparison with those in the OVX-induced estrogen deficiency group. As a result, liver injury was also attenuated with reduced levels of alanine aminotransferase and aspartate transaminase. In addition, our study found that ASTX supplementation decreased hepatic osteoprotegerin (OPG) in vivo, a possible factor that contributes to NASH development. In vitro, this study further confirmed that ASTX has an inhibitory effect on the secretion of OPG in LX-2 human hepatic stellate cells. CONCLUSIONS Our findings suggest that ASTX alleviates CDHF-OVX-induced pathohistological NASH with downregulated OPG, possibly via suppression of the transforming growth factor beta pathway. ASTX could has promise for use in postmenopausal women diagnosed with NASH.
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Affiliation(s)
- Meng Zhao
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Lingyun Ma
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Takashi Honda
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Asuka Kato
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan.,ITOCHU Collaborative Research-Molecular Targeted Cancer Treatment for Next Generation, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Taichi Ohshiro
- ITOCHU Collaborative Research-Molecular Targeted Cancer Treatment for Next Generation, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Shinya Yokoyama
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Kenta Yamamoto
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Takanori Ito
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Norihiro Imai
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Yoji Ishizu
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Masanao Nakamura
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Hiroki Kawashima
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Noriko M Tsuji
- Division of Microbiology, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo, Japan.,Division of Immune Homeostasis, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo, Japan.,Department of Food Science, Jumonji University, Saitama, Japan
| | - Masatoshi Ishigami
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan.,Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, 113-0033, Japan
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25
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Estrogen as a key regulator of energy homeostasis and metabolic health. Biomed Pharmacother 2022; 156:113808. [DOI: 10.1016/j.biopha.2022.113808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 10/02/2022] [Accepted: 10/03/2022] [Indexed: 11/23/2022] Open
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26
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Kamiya A, Ida K. Liver Injury and Cell Survival in Non-Alcoholic Steatohepatitis Regulated by Sex-Based Difference through B Cell Lymphoma 6. Cells 2022; 11:cells11233751. [PMID: 36497010 PMCID: PMC9737870 DOI: 10.3390/cells11233751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 11/14/2022] [Accepted: 11/20/2022] [Indexed: 11/25/2022] Open
Abstract
The liver is a crucial organ for maintaining homeostasis in living organisms and is the center of various metabolic functions. Therefore, abnormal metabolic activity, as in metabolic syndrome, leads to pathological conditions, such as abnormal accumulation of lipids in the liver. Inflammation and cell death are induced by several stresses in the fatty liver, namely steatohepatitis. In recent years, an increase in non-alcoholic steatohepatitis (NASH), which is not dependent on excessive alcohol intake, has become an issue as a major cause of liver cirrhosis and liver cancer. There are several recent findings on functional sex-based differences, NASH, and cell stress and death in the liver. In particular, NASH-induced liver injury and tumorigeneses were suppressed by B cell lymphoma 6, the transcriptional factor regulating sex-based liver functional gene expression. In this review, we discuss cell response to stress and lipotoxicity in NASH and its regulatory mechanisms.
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Affiliation(s)
- Akihide Kamiya
- Correspondence: ; Tel.: +81-463-93-1121 (ext. 2783); Fax: +81-463-95-3522
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27
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Kuang M, Sheng G, Hu C, Lu S, Peng N, Zou Y. The value of combining the simple anthropometric obesity parameters, Body Mass Index (BMI) and a Body Shape Index (ABSI), to assess the risk of non-alcoholic fatty liver disease. Lipids Health Dis 2022; 21:104. [PMID: 36266655 PMCID: PMC9585710 DOI: 10.1186/s12944-022-01717-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 10/07/2022] [Accepted: 10/13/2022] [Indexed: 11/15/2022] Open
Abstract
Background Body mass index (BMI) and A Body Shape Index (ABSI) are current independent risk factors for non-alcoholic fatty liver disease (NAFLD). The aim of this study was to explore the value of combining these two most common obesity indexes in identifying NAFLD. Methods The subjects in this study were 14,251 individuals from the NAfld in the Gifu Area, Longitudinal Analysis (NAGALA) cohort who underwent routine health examination. We integrated BMI with WC and with ABSI to construct 6 combined obesity indicators—obesity phenotypes, the combined anthropometric risk index (ARI) for BMI and ABSI, optimal proportional combination OBMI+WC and OBMI+ABSI, and multiplicative combination BMI*WC and BMI*ABSI. Several multivariable logistic regression models were established to evaluate the relationship between BMI, WC, ABSI, and the above six combined indicators and NAFLD; receiver operating characteristic (ROC) curves were drawn to compare the ability of each obesity indicator to identify NAFLD. Results A total of 2,507 (17.59%) subjects were diagnosed with NAFLD. BMI, WC, ABSI, and all other combined obesity indicators were significantly and positively associated with NAFLD in the current study, with BMI*WC having the strongest correlation with NAFLD in female subjects (OR per SD increase: 3.13) and BMI*ABSI having the strongest correlation in male subjects (OR per SD increase: 2.97). ROC analysis showed that ARI and OBMI+ABSI had the best diagnostic performance in both sexes, followed by BMI*WC (area under the curve: female 0.8912; male 0.8270). After further age stratification, it was found that ARI and multiplicative indicators (BMI*WC, BMI*ABSI) and optimal proportional combination indicators (OBMI+WC, OBMI+ABSI) significantly improved the NAFLD risk identification ability of the basic anthropometric parameters in middle-aged females and young and middle-aged males. Conclusion In the general population, BMI combined with ABSI best identified obesity-related NAFLD risk and was significantly better than BMI or WC, or ABSI. We find that ARI and the multiplicative combined indicators BMI*WC and BMI*ABSI further improved risk prediction and may be proposed for possible use in clinical practice. Supplementary Information The online version contains supplementary material available at 10.1186/s12944-022-01717-8.
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Affiliation(s)
- Maobin Kuang
- Medical College of Nanchang University, Nanchang of Jiangxi, 330006, Nanchang, China.,Department of Cardiology, Jiangxi Provincial People's Hospital, 330006, Nanchang, Jiangxi, China
| | - Guotai Sheng
- Department of Cardiology, Jiangxi Provincial People's Hospital, 330006, Nanchang, Jiangxi, China
| | - Chong Hu
- Department of Gastroenterology, Jiangxi Provincial People's Hospital, 330006, Nanchang, Jiangxi, China
| | - Song Lu
- Medical College of Nanchang University, Nanchang of Jiangxi, 330006, Nanchang, China.,Department of Cardiology, Jiangxi Provincial People's Hospital, 330006, Nanchang, Jiangxi, China
| | - Nan Peng
- Medical College of Nanchang University, Nanchang of Jiangxi, 330006, Nanchang, China.,Department of Cardiology, Jiangxi Provincial People's Hospital, 330006, Nanchang, Jiangxi, China
| | - Yang Zou
- Jiangxi Cardiovascular Research Institute, Jiangxi Provincial People's Hospital, 330006, Nanchang, Jiangxi, China.
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28
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Association of age at first birth and risk of non-alcoholic fatty liver disease in women: evidence from the NHANES. Hepatol Int 2022; 17:303-312. [PMID: 36227515 DOI: 10.1007/s12072-022-10429-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 09/13/2022] [Indexed: 11/04/2022]
Abstract
BACKGROUND Numerous studies have suggested that age at first birth (AFB) is inversely associated with metabolic diseases, but positively associated with liver cancer in women. Non-alcoholic fatty liver disease (NAFLD) is a canonical example of metabolic dysfunction and inflammation-based liver disease, while the association between AFB and the risk of NAFLD remains unclear. We aimed to investigate the association between AFB and the odds of NAFLD in women. METHODS Women older than 20 years at the time of the survey were analyzed using National Health and Nutrition Examination Survey (NHANES) data from 1999 to 2018 in the US. AFB was obtained with self-administered questionnaires. NAFLD was diagnosed as fatty liver index (FLI) ≥ 60. Odds ratios (ORs) and 95% confidence intervals (CI) were estimated using logistic regression models. RESULTS Of the 12,188 women included in this study, 5670 (46.5%) had NAFLD. Compared to individuals with AFB of 30-32 years old (reference group), the fully adjusted ORs and 95% CI in women with AFB < 18, 18-20, 21-23, and 24-26 years were 1.52 (95% CI 1.14, 2.03), 1.60 (95% CI 1.21, 2.11), 1.40 (95% CI 1.06, 1.84), and 1.33 (95% CI 1.01-1.76), respectively. Yet there was no significant difference between AFB of 27-29, 33-35, or > 35 years compared to the reference group. CONCLUSIONS Women with younger AFB have higher odds of NAFLD in later life. Policymakers should consider focusing on those with earlier AFB for screening and prevention of NAFLD.
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29
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Xu L, Yuan Y, Che Z, Tan X, Wu B, Wang C, Xu C, Xiao J. The Hepatoprotective and Hepatotoxic Roles of Sex and Sex-Related Hormones. Front Immunol 2022; 13:939631. [PMID: 35860276 PMCID: PMC9289199 DOI: 10.3389/fimmu.2022.939631] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 06/13/2022] [Indexed: 12/18/2022] Open
Abstract
Most liver diseases, including acute liver injury, drug-induced liver injury, viral hepatitis, metabolic liver diseases, and end-stage liver diseases, are strongly linked with hormonal influences. Thus, delineating the clinical manifestation and underlying mechanisms of the “sexual dimorphism” is critical for providing hints for the prevention, management, and treatment of those diseases. Whether the sex hormones (androgen, estrogen, and progesterone) and sex-related hormones (gonadotrophin-releasing hormone, luteinizing hormone, follicle-stimulating hormone, and prolactin) play protective or toxic roles in the liver depends on the biological sex, disease stage, precipitating factor, and even the psychiatric status. Lifestyle factors, such as obesity, alcohol drinking, and smoking, also drastically affect the involving mechanisms of those hormones in liver diseases. Hormones deliver their hepatic regulatory signals primarily via classical and non-classical receptors in different liver cell types. Exogenous sex/sex-related hormone therapy may serve as a novel strategy for metabolic liver disease, cirrhosis, and liver cancer. However, the undesired hormone-induced liver injury should be carefully studied in pre-clinical models and monitored in clinical applications. This issue is particularly important for menopause females with hormone replacement therapy (HRT) and transgender populations who want to receive gender-affirming hormone therapy (GAHT). In conclusion, basic and clinical studies are warranted to depict the detailed hepatoprotective and hepatotoxic mechanisms of sex/sex-related hormones in liver disease. Prolactin holds a promising perspective in treating metabolic and advanced liver diseases.
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Affiliation(s)
- Linlin Xu
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yuan Yuan
- Clinical Medicine Research Institute, Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Zhaodi Che
- Clinical Medicine Research Institute, Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Xiaozhi Tan
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Bin Wu
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Cunchuan Wang
- Clinical Medicine Research Institute, Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Chengfang Xu
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- *Correspondence: Chengfang Xu, ; Jia Xiao,
| | - Jia Xiao
- Clinical Medicine Research Institute, Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
- *Correspondence: Chengfang Xu, ; Jia Xiao,
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30
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Montefusco D, Jamil M, Maczis MA, Schroeder W, Levi M, Ranjit S, Allegood J, Bandyopadhyay D, Retnam R, Spiegel S, Cowart LA. Sphingosine Kinase 1 Mediates Sexual Dimorphism in Fibrosis in a Mouse Model of NASH. Mol Metab 2022; 62:101523. [PMID: 35671973 PMCID: PMC9194589 DOI: 10.1016/j.molmet.2022.101523] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 05/04/2022] [Accepted: 05/25/2022] [Indexed: 11/17/2022] Open
Abstract
OBJECTIVE Men with non-alcoholic fatty liver disease (NAFLD) are more likely to progress to nonalcoholic steatohepatitis (NASH) and liver fibrosis than women. However, the underlying molecular mechanisms of this dimorphism is unclear. We have previously shown that mice with global deletion of SphK1, the enzyme that produces the bioactive sphingolipid metabolite sphingosine 1-phosphate (S1P), were protected from development of NASH. The aim of this study was to elucidate the role of hepatocyte-specific SphK1 in development of NASH and to compare its contribution to hepatosteatosis in male and female mice. RESULTS We generated hepatocyte-specific SphK1 knockout mice (SphK1-hKO). Unlike the global knockout, SphK1-hKO male mice were not protected from diet-induced steatosis, inflammation, or fibrogenesis. In contrast, female SphK1-hKO mice were protected from inflammation. Surprisingly, however, in these female mice, there was a ∼10-fold increase in the fibrosis markers Col1α1 and 2-3 fold induction of alpha smooth muscle actin and the pro-fibrotic chemokine CCL5. Because increased fibrosis in female SphK1-hKO mice occurred despite an attenuated inflammatory response, we investigated the crosstalk between hepatocytes and hepatic stellate cells, central players in fibrosis. We found that estrogen stimulated release of S1P from female hepatocytes preventing TGFβ-induced expression of Col1α1 in HSCs via S1PR3. CONCLUSIONS The results revealed a novel pathway of estrogen-mediated cross-talk between hepatocytes and HSCs that may contribute to sex differences in NAFLD through an anti-fibrogenic function of the S1P/S1PR3 axis. This pathway is susceptible to pharmacologic manipulation, which may lead to novel therapeutic strategies.
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Affiliation(s)
- David Montefusco
- Virginia Commonwealth University, Department of Biochemistry and Molecular Biology, VA, USA.
| | - Maryam Jamil
- Virginia Commonwealth University, Department of Biochemistry and Molecular Biology, VA, USA
| | - Melissa A Maczis
- Virginia Commonwealth University, Department of Biochemistry and Molecular Biology, VA, USA
| | - William Schroeder
- Virginia Commonwealth University, Department of Biochemistry and Molecular Biology, VA, USA
| | - Moshe Levi
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, USA
| | - Suman Ranjit
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, USA
| | - Jeremy Allegood
- Virginia Commonwealth University, Department of Biochemistry and Molecular Biology, VA, USA
| | | | - Reuben Retnam
- Virginia Commonwealth University Department of Biostatistics, VA, USA
| | - Sarah Spiegel
- Virginia Commonwealth University, Department of Biochemistry and Molecular Biology, VA, USA
| | - L Ashley Cowart
- Virginia Commonwealth University, Department of Biochemistry and Molecular Biology, VA, USA; Hunter Holmes McGuire VAMC, Richmond, VA, USA
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31
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Sandovici I, Fernandez-Twinn DS, Hufnagel A, Constância M, Ozanne SE. Sex differences in the intergenerational inheritance of metabolic traits. Nat Metab 2022; 4:507-523. [PMID: 35637347 DOI: 10.1038/s42255-022-00570-4] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 04/05/2022] [Indexed: 02/02/2023]
Abstract
Strong evidence suggests that early-life exposures to suboptimal environmental factors, including those in utero, influence our long-term metabolic health. This has been termed developmental programming. Mounting evidence suggests that the growth and metabolism of male and female fetuses differ. Therefore, sexual dimorphism in response to pre-conception or early-life exposures could contribute to known sex differences in susceptibility to poor metabolic health in adulthood. However, until recently, many studies, especially those in animal models, focused on a single sex, or, often in the case of studies performed during intrauterine development, did not report the sex of the animal at all. In this review, we (a) summarize the evidence that male and females respond differently to a suboptimal pre-conceptional or in utero environment, (b) explore the potential biological mechanisms that underlie these differences and (c) review the consequences of these differences for long-term metabolic health, including that of subsequent generations.
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Affiliation(s)
- Ionel Sandovici
- Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK
- Department of Obstetrics and Gynaecology and National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
| | - Denise S Fernandez-Twinn
- Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - Antonia Hufnagel
- Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - Miguel Constância
- Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
- Department of Obstetrics and Gynaecology and National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK.
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
| | - Susan E Ozanne
- Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
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32
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Kim W. Chronic Liver Disease. SEX/GENDER-SPECIFIC MEDICINE IN THE GASTROINTESTINAL DISEASES 2022:209-227. [DOI: 10.1007/978-981-19-0120-1_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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33
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Jiang X, Li L, Xue HY. The impact of body position and exercise on the measurement of liver Young's modulus by real-time shear wave elastography. Technol Health Care 2021; 30:445-454. [PMID: 34657862 DOI: 10.3233/thc-213218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND In the past ten years, liver biopsies have been used as a method to accurately diagnose the stage of fibrosis. OBJECTIVE This study aimed to evaluate whether body position and exercise affect the measurement of liver Young's modulus of healthy volunteers by real-time shear wave elastography (RT-SWE). METHODS RT-SWE was used to measure liver Young's modulus in the supine and left lateral positions of 70 healthy volunteers at rest and measure the liver Young's modulus in the lying position before exercise, and at zero, five, and ten minutes of rest after exercise. RESULTS The liver Young's modulus in the left lateral position was significantly higher than in the supine position (P< 0.05), and the measured value in the supine position was more stable than the left lateral position. The liver Young's modulus measured at zero minutes after exercise was significantly higher than that measured before exercise (P< 0.05). The liver Young's modulus measured at five minutes after exercise was significantly higher than that measured at zero minutes after exercise (P<0.05) and was not statistically different from the measured value before exercise (P> 0.05). The liver Young's modulus measured at ten minutes after exercise was significantly higher from that measured at zero minutes after exercise (P< 0.05) and was not statistically different from the measured value at five minutes after exercise (P> 0.05). CONCLUSION Body position and exercise have a significant impact on the measurement of liver Young's modulus. It is recommended that the examinees take a supine position during the measurement, and measurement should be conducted at least ten minutes after exercise.
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Kim M, Hur S, Kim KH, Cho Y, Kim K, Kim HR, Nam KT, Lim KM. A New Murine Liver Fibrosis Model Induced by Polyhexamethylene Guanidine-Phosphate. Biomol Ther (Seoul) 2021; 30:126-136. [PMID: 34580237 PMCID: PMC8902451 DOI: 10.4062/biomolther.2021.120] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 08/12/2021] [Accepted: 08/13/2021] [Indexed: 11/05/2022] Open
Abstract
Liver fibrosis is part of the wound healing process to help the liver recover from the injuries caused by various liver-damaging insults. However, liver fibrosis often progresses to life-threatening cirrhosis and hepatocellular carcinoma. To overcome the limitations of current in vivo liver fibrosis models for studying the pathophysiology of liver fibrosis and establishing effective treatment strategies, we developed a new mouse model of liver fibrosis using polyhexamethylene guanidine phosphate (PHMG-p), a humidifier sterilizer known to induce lung fibrosis in humans. Male C57/BL6 mice were intraperitoneally injected with PHMG-p (0.03% and 0.1%) twice a week for 5 weeks. Subsequently, liver tissues were examined histologically and RNA-sequencing was performed to evaluate the expression of key genes and pathways affected by PHMG-p. PHMG-p injection resulted in body weight loss of ~15% and worsening of physical condition. Necropsy revealed diffuse fibrotic lesions in the liver with no effect on the lungs. Histology, collagen staining, immunohistochemistry for smooth muscle actin and collagen, and polymerase chain reaction analysis of fibrotic genes revealed that PHMG-p induced liver fibrosis in the peri-central, peri-portal, and capsule regions. RNA-sequencing revealed that PHMG-p affected several pathways associated with human liver fibrosis, especially with upregulation of lumican and IRAK3, and downregulation of GSTp1 and GSTp2, which are closely involved in liver fibrosis pathogenesis. Collectively we demonstrated that the PHMG-p-induced liver fibrosis model can be employed to study human liver fibrosis.
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Affiliation(s)
- Minjeong Kim
- College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Sumin Hur
- Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, College of Medicine, Yonsei University, Seoul 03722, Republic of Korea
| | - Kwang H Kim
- Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, College of Medicine, Yonsei University, Seoul 03722, Republic of Korea
| | - Yejin Cho
- Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, College of Medicine, Yonsei University, Seoul 03722, Republic of Korea
| | - Keunyoung Kim
- College of Pharmacy, Kangwon National University, Chuncheon 24341, Republic of Korea
| | - Ha Ryong Kim
- College of Pharmacy, Daegu Catholic University, Daegu 38430, Republic of Korea
| | - Ki Taek Nam
- Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, College of Medicine, Yonsei University, Seoul 03722, Republic of Korea
| | - Kyung-Min Lim
- College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea
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35
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Vilar-Gomez E, Pirola CJ, Sookoian S, Wilson LA, Liang T, Chalasani N. The Protection Conferred by HSD17B13 rs72613567 Polymorphism on Risk of Steatohepatitis and Fibrosis May Be Limited to Selected Subgroups of Patients With NAFLD. Clin Transl Gastroenterol 2021; 12:e00400. [PMID: 34506332 PMCID: PMC8437218 DOI: 10.14309/ctg.0000000000000400] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 08/05/2021] [Indexed: 12/11/2022] Open
Abstract
INTRODUCTION Our study aimed to explore how PNPLA3 rs738409 or phenotypic risk factors may moderate the relationship between HSD17B13 rs72613567 and risk of steatohepatitis and fibrosis. METHODS This analysis consisted of 1,153 non-Hispanic whites with biopsy-proven nonalcoholic fatty liver disease enrolled in the nonalcoholic steatohepatitis Clinical Research Network studies. Nonalcoholic fatty liver disease severity was determined by liver histology scored centrally according to the nonalcoholic steatohepatitis Clinical Research Network criteria. Moderation and logistic regression analyses were performed to identify the influence of moderators (PNPLA3 rs738409, age, sex, body mass index, and diabetes) on the relationship between HSD17B13 rs72613567 and risk of steatohepatitis and fibrosis. RESULTS HSD17B13 rs72613567 genotype frequency was as follows: (-/-), 64%; (-/A), 30%; (A/A), 6%. Moderation analysis showed that the protective effect of HSD17B13 rs72613567 A-allele on risk of steatohepatitis remained only significant among patients with PNPLA3 rs738409 genotype CC (β coeff: -0.19, P = 0.019), women (β coeff: -0.18, P < 0.001), patients of age ≥ 45 years (β coeff: -0.18, P < 0.001), patients with body mass index ≥ 35 kg/m2 (β coeff: -0.17, P < 0.001), and patients with diabetes (β coeff: -0.18, P = 0.020). Among women, the protective effect of HSD17B131 rs72613567 A-allele on risk of steatohepatitis was stronger in those aged ≥ 51 years. Logistic regression-based sensitivity analysis including various important subgroups confirmed our observations. DISCUSSION The protection conferred by HSD17B13 rs72613567 A-allele on risk of steatohepatitis and fibrosis may be limited to selected subgroups of individuals who are aged ≥ 45 years, women and have class ≥ 2 obesity or diabetes, and those with PNPLA3 rs738409 CC genotype.
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Affiliation(s)
- Eduardo Vilar-Gomez
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Carlos J. Pirola
- Molecular Genetics and Biology of Complex Diseases, University of Buenos Aires-National Scientific and Technical Research Council (CONICET), Ciudad Autonoma de Buenos Aires, Argentina;
| | - Silvia Sookoian
- Department of Clinical and Molecular Hepatology, Institute of Medical Research (IDIM), University of Buenos Aires-National Scientific and Technical Research Council (CONICET), Ciudad Autonoma de Buenos Aires, Argentina
| | - Laura A. Wilson
- Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Tiebing Liang
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Naga Chalasani
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
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Königshofer P, Brusilovskaya K, Petrenko O, Hofer BS, Schwabl P, Trauner M, Reiberger T. Nuclear Receptors in Liver Fibrosis. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166235. [PMID: 34339839 DOI: 10.1016/j.bbadis.2021.166235] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 07/18/2021] [Accepted: 07/27/2021] [Indexed: 12/12/2022]
Abstract
Nuclear receptors are ligand-activated transcription factors that regulate gene expression of a variety of key molecular signals involved in liver fibrosis. The primary cellular driver of liver fibrogenesis are activated hepatic stellate cells. Different NRs regulate the hepatic expression of pro-inflammatory and pro-fibrogenic cytokines that promote the transformation of hepatic stellate cells into fibrogenic myofibroblasts. Importantly, nuclear receptors regulate gene expression circuits that promote hepatic fibrogenesis and/or allow liver fibrosis regression. In this review, we highlight the direct and indirect influence of nuclear receptors on liver fibrosis, with a focus on hepatic stellate cells, and discuss potential therapeutic effects of nuclear receptor modulation in regard to anti-fibrotic and anti-inflammatory effects. Further research on nuclear receptors-related signaling may lead to the clinical development of effective anti-fibrotic therapies for patients with liver disease.
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Affiliation(s)
- Philipp Königshofer
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Experimental Hepatic Hemodynamic Lab (HEPEX), Medical University of Vienna, Vienna, Austria; Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Ksenia Brusilovskaya
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Experimental Hepatic Hemodynamic Lab (HEPEX), Medical University of Vienna, Vienna, Austria; Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Oleksandr Petrenko
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Experimental Hepatic Hemodynamic Lab (HEPEX), Medical University of Vienna, Vienna, Austria; Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Benedikt Silvester Hofer
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Experimental Hepatic Hemodynamic Lab (HEPEX), Medical University of Vienna, Vienna, Austria; Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Philipp Schwabl
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Experimental Hepatic Hemodynamic Lab (HEPEX), Medical University of Vienna, Vienna, Austria; Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Experimental Hepatic Hemodynamic Lab (HEPEX), Medical University of Vienna, Vienna, Austria; Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
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Carruba G. Estrogens in Hepatocellular Carcinoma: Friends or Foes? Cancers (Basel) 2021; 13:cancers13092085. [PMID: 33925807 PMCID: PMC8123464 DOI: 10.3390/cancers13092085] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 04/22/2021] [Accepted: 04/23/2021] [Indexed: 01/06/2023] Open
Abstract
Simple Summary Today, we know that estrogen hormones are required for the development and function of many organs, such as the liver, in both males and females. However, in some circumstances, estrogen excess may be implicated in the appearance of various chronic diseases, including cancer. This review will inspect the results of several studies to better understand the mechanisms responsible for estrogens to change from protective into harmful hormones in human liver. Abstract Estrogens are recognized as key players in physiological regulation of various, classical and non-classical, target organs, and tissues, including liver development, homeostasis, and function. On the other hand, multiple, though dispersed, experimental evidence is highly suggestive for the implication of estrogen in development and progression of hepatocellular carcinoma. In this paper, data from our own studies and the current literature are reviewed to help understanding this apparent discrepancy.
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Affiliation(s)
- Giuseppe Carruba
- Servizio di Internazionalizzazione e Ricerca Sanitaria (SIRS), Azienda di Rilievo Nazionale e di Alta Specializzazione (ARNAS)-Civico, Di Cristina, Benfratelli-Palermo, Piazza N. Leotta 2, 90127 Palermo, Italy
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38
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Lu J, Gong Y, Wei X, Yao Z, Yang R, Xin J, Gao L, Shao S. Changes in hepatic triglyceride content with the activation of ER stress and increased FGF21 secretion during pregnancy. Nutr Metab (Lond) 2021; 18:40. [PMID: 33849585 PMCID: PMC8045396 DOI: 10.1186/s12986-021-00570-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Accepted: 04/03/2021] [Indexed: 12/15/2022] Open
Abstract
Background To meet the needs of foetal growth and development, marked changes in lipid profiles occur during pregnancy. Abnormal lipid metabolism is often accompanied by adverse pregnancy outcomes, which seriously affect maternal and infant health. Further understanding of the mechanism of lipid metabolism during pregnancy would be helpful to reduce the incidence of adverse pregnancy outcomes. Methods Pregnant mice were euthanized in the virgin (V) state, on day 5 of pregnancy (P5), on day 12 of pregnancy (P12), on day 19 of pregnancy (P19) and on lactation day 2 (L2). Body weight and energy expenditure were assessed to evaluate the general condition of the mice. Triglyceride (TG) levels, the cholesterol content in the liver, liver histopathology, serum lipid profiles, serum β-hydroxybutyrate levels, fibroblast growth factor-21 (FGF21) levels and the levels of relevant target genes were analysed. Results During early pregnancy, anabolism was found to play a major role in liver lipid deposition. In contrast, advanced pregnancy is an overall catabolic condition associated with both increased energy expenditure and reduced lipogenesis. Moreover, the accumulation of hepatic TG did not appear until P12, after the onset of endoplasmic reticulum (ER) stress on P5. Then, catabolism was enhanced, and FGF21 secretion was increased in the livers of female mice in late pregnancy. We further found that the expression of sec23a, which as the coat protein complex II (COPII) vesicle coat proteins regulates the secretion of FGF21, in the liver was decreased on P19. Conclusion With the activation of ER stress and increased FGF21 secretion during pregnancy, the hepatic TG content changes, suggesting that ER stress and FGF21 may play an important role in balancing lipid homeostasis and meeting maternal and infant energy requirements in late pregnancy.
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Affiliation(s)
- Jiayu Lu
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 544, Jing 4 Rd., Jinan, 250021, Shandong, China.,Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, 250021, Shandong, China.,Shandong Institute of Endocrine and Metabolic Disease, Jinan, 250021, Shandong, China
| | - Ying Gong
- Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China.,Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, 250021, Shandong, China.,Shandong Institute of Endocrine and Metabolic Disease, Jinan, 250021, Shandong, China
| | - Xinhong Wei
- Shandong Medical Imaging Research Institute, Shandong University, Jinan, 250021, Shandong, China
| | - Zhenyu Yao
- Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China.,Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, 250021, Shandong, China.,Shandong Institute of Endocrine and Metabolic Disease, Jinan, 250021, Shandong, China
| | - Rui Yang
- Experimental Animal Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Jinxing Xin
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 544, Jing 4 Rd., Jinan, 250021, Shandong, China.,Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, 250021, Shandong, China.,Shandong Institute of Endocrine and Metabolic Disease, Jinan, 250021, Shandong, China
| | - Ling Gao
- Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, 250021, Shandong, China.,Shandong Institute of Endocrine and Metabolic Disease, Jinan, 250021, Shandong, China.,Scientific Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Shanshan Shao
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 544, Jing 4 Rd., Jinan, 250021, Shandong, China. .,Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, 250021, Shandong, China. .,Shandong Institute of Endocrine and Metabolic Disease, Jinan, 250021, Shandong, China.
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Managing cardiometabolic risk factors across a woman's lifespan: A lipidologist's perspective. J Clin Lipidol 2021; 15:423-430. [PMID: 33836983 DOI: 10.1016/j.jacl.2021.03.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 03/10/2021] [Accepted: 03/16/2021] [Indexed: 12/14/2022]
Abstract
A recent rise in atherosclerotic cardiovascular disease (ASCVD) mortality in women warrants a heightened focus on the cardiometabolic risk factors that are closely tied to increasing trends in obesity and suboptimal lifestyle. Polycystic ovarian syndrome (PCOS), adverse pregnancy outcomes (APOs) and nonalcoholic fatty liver disease (NAFLD) are often manifestations of cardiometabolic disease that convey cardiovascular risk requiring recognition foremost, as well as a targeted approach to treatment. Similarly, menopause is a time to reflect on a woman's cardiovascular risk as multiple cardiometabolic changes occur during this time. Contraceptives and menopausal replacement therapy (MRT) should be considered along with a woman's individual thrombotic and cardiovascular risk. Clinicians should be attuned to cardiometabolic risk factors throughout a woman's lifespan and familiar with strategies to reduce cardiovascular risk.
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40
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Shen M, Xu M, Zhong F, Crist MC, Prior AB, Yang K, Allaire DM, Choueiry F, Zhu J, Shi H. A Multi-Omics Study Revealing the Metabolic Effects of Estrogen in Liver Cancer Cells HepG2. Cells 2021; 10:cells10020455. [PMID: 33672651 PMCID: PMC7924215 DOI: 10.3390/cells10020455] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 02/14/2021] [Accepted: 02/16/2021] [Indexed: 12/19/2022] Open
Abstract
Hepatocellular carcinoma (HCC) that is triggered by metabolic defects is one of the most malignant liver cancers. A much higher incidence of HCC among men than women suggests the protective roles of estrogen in HCC development and progression. To begin to understand the mechanisms involving estrogenic metabolic effects, we compared cell number, viability, cytotoxicity, and apoptosis among HCC-derived HepG2 cells that were treated with different concentrations of 2-deoxy-d-glucose (2-DG) that blocks glucose metabolism, oxamate that inhibits lactate dehydrogenase and glycolysis, or oligomycin that blocks ATP synthesis and mitochondrial oxidative phosphorylation. We confirmed that HepG2 cells primarily utilized glycolysis followed by lactate fermentation, instead of mitochondrial oxidative phosphorylation, for cell growth. We hypothesized that estrogen altered energy metabolism via its receptors to carry out its anticancer effects in HepG2 cells. We treated cells with 17β-estradiol (E2), 1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT) an estrogen receptor (ER) α (ERα) agonist, or 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN), an ERβ agonist. We then used transcriptomic and metabolomic analyses and identified differentially expressed genes and unique metabolite fingerprints that are produced by each treatment. We further performed integrated multi-omics analysis, and identified key genes and metabolites in the gene–metabolite interaction contributed by E2 and ER agonists. This integrated transcriptomic and metabolomic study suggested that estrogen acts on estrogen receptors to suppress liver cancer cell growth via altering metabolism. This is the first exploratory study that comprehensively investigated estrogen and its receptors, and their roles in regulating gene expression, metabolites, metabolic pathways, and gene–metabolite interaction in HCC cells using bioinformatic tools. Overall, this study provides potential therapeutic targets for future HCC treatment.
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Affiliation(s)
- Minqian Shen
- Department of Biology, Miami University, Oxford, OH 45056, USA; (M.S.); (M.X.); (M.C.C.); (A.B.P.); (D.M.A.)
| | - Mengyang Xu
- Department of Biology, Miami University, Oxford, OH 45056, USA; (M.S.); (M.X.); (M.C.C.); (A.B.P.); (D.M.A.)
- Department of Chemistry and Biochemistry, Miami University, Oxford, OH 45056, USA; (F.Z.); (K.Y.)
| | - Fanyi Zhong
- Department of Chemistry and Biochemistry, Miami University, Oxford, OH 45056, USA; (F.Z.); (K.Y.)
| | - McKenzie C. Crist
- Department of Biology, Miami University, Oxford, OH 45056, USA; (M.S.); (M.X.); (M.C.C.); (A.B.P.); (D.M.A.)
| | - Anjali B. Prior
- Department of Biology, Miami University, Oxford, OH 45056, USA; (M.S.); (M.X.); (M.C.C.); (A.B.P.); (D.M.A.)
| | - Kundi Yang
- Department of Chemistry and Biochemistry, Miami University, Oxford, OH 45056, USA; (F.Z.); (K.Y.)
| | - Danielle M. Allaire
- Department of Biology, Miami University, Oxford, OH 45056, USA; (M.S.); (M.X.); (M.C.C.); (A.B.P.); (D.M.A.)
| | - Fouad Choueiry
- Department of Human Sciences, College of Education and Human Ecology, Columbus, OH 43210, USA;
- James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
| | - Jiangjiang Zhu
- Department of Human Sciences, College of Education and Human Ecology, Columbus, OH 43210, USA;
- James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
- Correspondence: (J.Z.); (H.S.); Tel.: +1-614-685-2226 (J.Z.); +1-513-529-3162 (H.S.)
| | - Haifei Shi
- Department of Biology, Miami University, Oxford, OH 45056, USA; (M.S.); (M.X.); (M.C.C.); (A.B.P.); (D.M.A.)
- Correspondence: (J.Z.); (H.S.); Tel.: +1-614-685-2226 (J.Z.); +1-513-529-3162 (H.S.)
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Samadi‐Noshahr Z, Hadjzadeh M, Moradi‐Marjaneh R, Khajavi‐Rad A. The hepatoprotective effects of fennel seeds extract and trans-Anethole in streptozotocin-induced liver injury in rats. Food Sci Nutr 2021; 9:1121-1131. [PMID: 33598196 PMCID: PMC7866591 DOI: 10.1002/fsn3.2090] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 12/08/2020] [Accepted: 12/14/2020] [Indexed: 12/12/2022] Open
Abstract
Hypoglycemic, anti-inflammatory, and antioxidant activities of fennel have been recorded in numerous investigations. The study aimed to evaluate the protective effects of fennel or its active component trans-Anethole (TA) on streptozotocin-induced liver injury in rats. Rats were injected with a single dose of STZ (65 mg/kg) and treated with fennel (200 and 400 mg/kg), TA (80 mg/kg), or metformin (300 mg/kg) for 35 days. Serum lipid profile and liver enzyme activity (aminotransferases), oxidative stress markers, and the degree of fibrosis in the liver tissue were assessed. Both fennel and TA decreased blood glucose levels, reduced liver enzyme activity, food, and water intake, and intensity of weight loss, reduced serum triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), and increased high-density lipoprotein cholesterol (HDL-c). Additionally, fennel and TA significantly reduced MDA concentration while increased CAT activity and thiol content and reduced the degree of injury and fibrosis in the liver of diabetic rats. Our results suggest that fennel seed extract and its active compound TA are able to protect the liver against diabetes-induced hepatic injury in rats, probably via hypoglycemic and antioxidant effects.
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Affiliation(s)
- Zahra Samadi‐Noshahr
- Student Research CommitteeFaculty of MedicineMashhad University of Medical SciencesMashhadIran
- Department of PhysiologyFaculty of MedicineMashhad University of Medical SciencesMashhadIran
| | - Mousa‐Al‐Reza Hadjzadeh
- Department of PhysiologyFaculty of MedicineMashhad University of Medical SciencesMashhadIran
- Neurogenic Inflammation Research CenterMashhad University of Medical SciencesMashhadIran
| | | | - Abolfazl Khajavi‐Rad
- Department of PhysiologyFaculty of MedicineMashhad University of Medical SciencesMashhadIran
- Neurogenic Inflammation Research CenterMashhad University of Medical SciencesMashhadIran
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Sarkar M, Brady CW, Fleckenstein J, Forde KA, Khungar V, Molleston JP, Afshar Y, Terrault NA. Reproductive Health and Liver Disease: Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology 2021; 73:318-365. [PMID: 32946672 DOI: 10.1002/hep.31559] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 09/08/2020] [Indexed: 12/11/2022]
Affiliation(s)
- Monika Sarkar
- University of California, San Francisco, San Francisco, CA
| | | | | | | | | | - Jean P Molleston
- Indiana University and Riley Hospital for Children, Indianapolis, IN
| | - Yalda Afshar
- University of California, Los Angeles, Los Angeles, CA
| | - Norah A Terrault
- Keck School of Medicine, University of Southern California, Los Angeles, CA
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43
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Zhang M, Wang Y, Zhu G, Sun C, Wang J. Hepatoprotective effect and possible mechanism of phytoestrogen calycosin on carbon tetrachloride-induced liver fibrosis in mice. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2021; 394:189-204. [PMID: 32474674 DOI: 10.1007/s00210-020-01891-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 04/28/2020] [Indexed: 01/02/2023]
Abstract
The study was to explore the hepatoprotective effect and possible mechanism of calycosin on carbon tetrachloride (CCl4)-induced liver fibrosis in mice. Hepatic fibrosis was induced by intraperitoneal injection of CCl4 in C57BL/6 male mice. Serum alanine aminotransferase (ALT) and aspartate transaminase (AST) activity, superoxide dismutase (SOD) activity, and hydroxyproline (Hyp) and malondialdehyde (MDA) levels were determined by biochemical assays. Liver histopathology was assessed by H&E and Masson trichrome staining. The mRNA expressions of α-smooth muscle actin (α-SMA), collagen-I (Col-I), Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) were determined using qRT-PCR. The protein levels of α-SMA, Col-I, estrogen receptor α (ERα), estrogen receptor β (ERβ), tissue inhibitor of metalloproteinase-1 (TIMP-1), matrix metalloproteinase-1 (MMP-1), JAK2, phospho-JAK2 (p-JAK2), STAT3, and phospho-STAT3 (p-STAT3) were detected by Western blotting. The levels of α-SMA and ERβ were measured by immunohistochemistry. Calycosin significantly reduced liver index, MDA level, and ALT and AST activity and increased SOD activity. The α-SMA, Col-I, and Hyp of the calycosin group were significantly lower than those of the model group. Calycosin increased MMP-1 and inhibited TIMP-1 expression resulting in the improvement of MMP-1/TIMP-1 ratio. Importantly, calycosin improved ERβ protein expression, JAK2 and STAT3 mRNA expressions, p-JAK2/JAK2, and p-STAT3/STAT3 relative protein expressions. However, ERα, JAK2, and STAT3 protein expressions were relatively unchanged. Calycosin significantly inhibits liver fibrosis in mice, and its mechanism may involve the following: calycosin inhibits oxidative stress; calycosin inhibits collagen synthesis and balances MMP-1/TIMP-1 system; calycosin increases ERβ expression and activates JAK2-STAT3 pathway.
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Affiliation(s)
- Mengmeng Zhang
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, Anhui Province, China
| | - Yaxin Wang
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, Anhui Province, China
| | - Guannan Zhu
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, Anhui Province, China
| | - Cheng Sun
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, Anhui Province, China
| | - Jiajia Wang
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, Anhui Province, China.
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Li DK, Khan MR, Wang Z, Chongsrisawat V, Swangsak P, Teufel-Schäfer U, Engelmann G, Goldschmidt I, Baumann U, Tokuhara D, Cho Y, Rowland M, Mjelle AB, Ramm GA, Lewindon PJ, Witters P, Cassiman D, Ciuca IM, Prokop LD, Haffar S, Corey KE, Murad MH, Furuya KN, Bazerbachi F. Normal liver stiffness and influencing factors in healthy children: An individual participant data meta-analysis. Liver Int 2020; 40:2602-2611. [PMID: 32901449 DOI: 10.1111/liv.14658] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 08/20/2020] [Accepted: 08/22/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Although transient elastography (TE) is used to determine liver stiffness as a surrogate to hepatic fibrosis, the normal range in children is not well defined. We performed a systematic review and individual participant data (IPD) meta-analysis to determine the range of liver stiffness in healthy children and evaluate the influence of important biological parameters. METHODS We pooled data from 10 studies that examined healthy children using TE. We divided 1702 children into two groups: ≥3 years (older group) and < 3 years of age (younger group). Univariate and multivariate linear regression models predicting liver stiffness were conducted. RESULTS After excluding children with obesity, diabetes, or abnormal liver tests, 652 children were analysed. Among older children, mean liver stiffness was 4.45 kPa (95% confidence interval 4.34-4.56), and increased liver stiffness was associated with age, sedation status, and S probe use. In the younger group, the mean liver stiffness was 4.79 kPa (95% confidence interval 4.46-5.12), and increased liver stiffness was associated with sedation status and Caucasian race. In a subgroup analysis, hepatic steatosis on ultrasound was significantly associated with increased liver stiffness. We define a reference range for normal liver stiffness in healthy children as 2.45-5.56 kPa. CONCLUSIONS We have established TE-derived liver stiffness ranges for healthy children and propose an upper limit of liver stiffness in healthy children to be 5.56 kPa. We have identified increasing age, use of sedation, probe size, and presence of steatosis on ultrasound as factors that can significantly increase liver stiffness.
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Affiliation(s)
- Darrick K Li
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Muhammad Rehan Khan
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of Illinois College of Medicine at Peoria, Children's Hospital of Illinois, Peoria, IL, USA
| | - Zhen Wang
- Evidence-Based Practice Center, Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN, USA
| | - Voranush Chongsrisawat
- Department of Pediatrics, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Panida Swangsak
- Department of Pediatrics, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Ulrike Teufel-Schäfer
- Department of Pediatrics and Adolescent Medicine, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | | | - Imeke Goldschmidt
- Division of Paediatric Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany
| | - Ulrich Baumann
- Division of Paediatric Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany.,Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom
| | - Daisuke Tokuhara
- Department of Pediatrics, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yuki Cho
- Department of Pediatrics, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Marion Rowland
- School of Medicine and Medical Science, University College Dublin, Dublin, Ireland
| | - Anders B Mjelle
- Department of Pediatric and Adolescent Medicine, Haukeland University Hospital, Bergen, Norway.,Department of Clinical Medicine, University of Bergen, Bergen, Norway.,National Centre for Ultrasound in Gastroenterology, Department of Medicine, Haukeland University Hospital, Bergen, Norway
| | - Grant A Ramm
- Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Peter J Lewindon
- Department of Gastroenterology, Hepatology and Liver Transplant, Queensland Children's Hospital, Brisbane, Australia
| | - Peter Witters
- Department of Paediatrics, University Hospitals Leuven, Leuven, Belgium
| | - David Cassiman
- Department of Gastroenterology-Hepatology and Metabolic Center, University of Leuven, Leuven, Belgium
| | - Ioana M Ciuca
- Pediatrics Department, University of Medicine and Pharmacy "Victor Babes", Timisoara, Romania
| | - Larry D Prokop
- Evidence-Based Practice Center, Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN, USA
| | - Samir Haffar
- Digestive Center for Diagnosis and Treatment, Damascus, Syrian Arab Republic
| | - Kathleen E Corey
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - M H Murad
- Evidence-Based Practice Center, Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN, USA
| | - Katryn N Furuya
- Department of Pediatrics, University of Wisconsin - Madison School of Medicine and Public Health, Madison, WI, USA
| | - Fateh Bazerbachi
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
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Seo D, Lee YH, Park S, Choi Y, Huh B, Lee E, Huh K, Kim S, Cha BS. Sarcopenia is associated with non-alcoholic fatty liver disease in men with type 2 diabetes. DIABETES & METABOLISM 2020; 46:362-369. [DOI: 10.1016/j.diabet.2019.10.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Revised: 10/17/2019] [Accepted: 10/22/2019] [Indexed: 02/07/2023]
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Critical role of estrogen in the progression of chronic liver diseases. Hepatobiliary Pancreat Dis Int 2020; 19:429-434. [PMID: 32299655 DOI: 10.1016/j.hbpd.2020.03.011] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Accepted: 03/19/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Estrogens regulate sexual function and also have a significant role in various pathophysiological processes. Estrogens have a non-reproductive role as the modulators of the immune system, growth, neuronal function, and metabolism. Estrogen receptors are expressed in the liver and their impaired expression and function are implicated with obesity and liver associated metabolic dysfunctions. The purpose of the current review is to discuss the disparity role of estrogens on several forms of liver diseases. DATA SOURCES A comprehensive search in PubMed and EMBASE was conducted using the keywords "estrogens and liver diseases", "estradiol and liver diseases", "hormones and liver diseases", "endocrine function in liver diseases", and "female hormones in liver diseases". Relevant papers published before September 30, 2019 were included. RESULTS The present review confirms the imperative role of estrogen in various forms of chronic liver diseases. Estrogens play a key role in maintaining homeostasis and make the liver less susceptible to several forms of chronic liver diseases in healthy premenopausal individuals. In contrast, clinical studies also showed increased estrogen levels with chronic liver diseases. CONCLUSIONS Several studies reported the protective role of estrogens in chronic liver diseases and this has been widely accepted and confirmed in experimental studies using ovariectomized rat models. However, in a few clinical studies, increased estrogen levels are also implicated in chronic liver diseases. Therefore, further studies are warranted at molecular level to explore the role of estrogen in various forms of chronic liver diseases.
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Influence of Gender and Reproductive Factors on Liver Fibrosis in Patients With Chronic Hepatitis B Infection. Clin Transl Gastroenterol 2020; 10:e00085. [PMID: 31651450 PMCID: PMC6884344 DOI: 10.14309/ctg.0000000000000085] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
INTRODUCTION: The role of reproductive factors in the development of chronic hepatitis B (CHB) remains unknown. We assessed the potential contributions of gender, menopausal status, and menarche age to liver fibrosis in CHB. METHODS: A cross-sectional prospective study included 716 women and 716 age-matched men with CHB who were not currently receiving antiviral therapy. Liver stiffness measurement using transient elastography was used to stage liver fibrosis as F0–F1 (<7.2 kPa), F ≥ 2 (7.2 kPa), F ≥ 3 (9.4 kPa), and F = 4 (12.2 kPa). Female patients were asked regarding their age at menarche and menopausal status using a questionnaire. RESULTS: Of the 716 women, 121 (16.9%) were postmenopausal, and 80 (11.2%) had advanced liver fibrosis. Multivariate logistic regression analysis showed that the postmenopausal status compared with the premenopausal status (odds ratio [OR] = 3.65–8.83; P < 0.05) and age at menarche of >14 years compared with <13 years (OR = 2.85–3.95; P < 0.05) were significantly associated with advanced fibrosis. Compared with premenopausal women, age-matched men had a higher OR for advanced fibrosis (P < 0.05). Compared with postmenopausal women, age-matched men did not show a significant difference in the degree of liver fibrosis (P > 0.05). Longitudinal data analysis showed that postmenopausal women (n = 31) were significantly less likely to undergo regression of liver fibrosis after antiviral treatment vs premenopausal women (n = 19) (26.3% vs 74.2%, respectively; P < 0.001). DISCUSSION: Menopause and late menarche aggravated liver fibrosis in untreated CHB, besides menopause delayed fibrosis regression under antiviral therapy. The protective effect of female gender against fibrosis was lost for postmenopausal women. TRANSLATIONAL IMPACT: It is important to consider menopausal status and age at menarche in establishing surveillance strategies among CHB females. Postmenopausal estrogen therapy may be considered for the prevention or treatment of liver fibrosis.
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Tobari M, Hashimoto E. Characteristic Features of Nonalcoholic Fatty Liver Disease in Japan with a Focus on the Roles of Age, Sex and Body Mass Index. Gut Liver 2020; 14:537-545. [PMID: 31887811 PMCID: PMC7492496 DOI: 10.5009/gnl19236] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 09/08/2019] [Accepted: 09/16/2019] [Indexed: 02/06/2023] Open
Abstract
This review provides an update on the characteristics of nonalcoholic fatty liver disease (NAFLD), with a focus on the effects of age, sex, and body mass index. Age is a risk factor for NAFLD progression; however, extremely old patients have unique features, namely, the associations between metabolic comorbidities and NAFLD are weaker and NAFLD is not a risk factor for mortality. The prevalence of NAFLD is higher in men than in premenopausal women, whereas the reverse is true after menopause. Thus, before menopause, estrogen may have protective effects against NAFLD. Our hospital data showed that over 25% of male patients with NAFLD and almost 40% of female patients with NAFLD, especially elderly patients, were nonobese. Although histological steatosis and activity were associated with body mass index, the prevalence of nonalcoholic steatohepatitis was not. The prevalence of advanced fibrosis showed a significant sex difference. Advanced fibrosis was significantly more frequent among severely obese men but the prevalence was lower among severely obese women. This difference could be because a substantial proportion of severely obese women were premenopausal; thus, estrogen may have much stronger effects on the development of fibrosis than on obesity. Further studies are required to develop tailored management strategies.
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Affiliation(s)
- Maki Tobari
- Department of Internal Medicine and Gastroenterology, Tokyo Women’s Medical University Yachiyo Medical Center, Chiba, Japan
| | - Etsuko Hashimoto
- Department of Internal Medicine and Gastroenterology, Tokyo Women’s Medical University, Tokyo, Japan
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Garate-Carrillo A, Gonzalez J, Ceballos G, Ramirez-Sanchez I, Villarreal F. Sex related differences in the pathogenesis of organ fibrosis. Transl Res 2020; 222:41-55. [PMID: 32289256 PMCID: PMC7721117 DOI: 10.1016/j.trsl.2020.03.008] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 03/05/2020] [Accepted: 03/09/2020] [Indexed: 12/11/2022]
Abstract
The development of organ fibrosis has garnered rising attention as multiple diseases of increasing and/or high prevalence appear to progress to the chronic stage. Such is the case for heart, kidney, liver, and lung where diseases such as diabetes, idiopathic/autoimmune disorders, and nonalcoholic liver disease appear to notably drive the development of fibrosis. Noteworthy is that the severity of these pathologies is characteristically compounded by aging. For these reasons, research groups and drug companies have identified fibrosis as a therapeutic target for which currently, there are essentially no effective options. Although a limited body of published studies are available, most literature indicates that in multiple organs, premenopausal women are protected from developing severe forms of fibrosis suggesting an important role for sex hormones in mitigating this process. Investigators have implemented relevant animal models of organ disease linked to fibrosis supporting in general, these observations. In vitro studies and transgenic animals models have also been used in an attempt to understand the role that sex hormones and related receptors play in the development of fibrosis. However, in the setting of chronic disease in some organs such as the heart older (postmenopausal) women within a few years can quickly approach men in disease severity and develop significant degrees of fibrosis. This review summarizes the current body of relevant literature and highlights the imperative need for a major focus to be placed on understanding the manner in which sex and the presence or absence of related hormones modulates cell phenotypes so as to allow for fibrosis to develop.
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Affiliation(s)
- Alejandra Garate-Carrillo
- Department of Medicine, School of Medicine, University of California, San Diego, California; Seccion de Estudios de Posgrado e Investigacion, Escuela Superior de Medicina, Instituto Politecnico Nacional, Mexico city, Mexico
| | - Julisa Gonzalez
- Department of Medicine, School of Medicine, University of California, San Diego, California
| | - Guillermo Ceballos
- Seccion de Estudios de Posgrado e Investigacion, Escuela Superior de Medicina, Instituto Politecnico Nacional, Mexico city, Mexico
| | - Israel Ramirez-Sanchez
- Department of Medicine, School of Medicine, University of California, San Diego, California; Seccion de Estudios de Posgrado e Investigacion, Escuela Superior de Medicina, Instituto Politecnico Nacional, Mexico city, Mexico
| | - Francisco Villarreal
- Department of Medicine, School of Medicine, University of California, San Diego, California; VA San Diego Health Care, San Diego, California.
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50
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Yuan L, Kardashian A, Sarkar M. NAFLD in women: Unique pathways, biomarkers and therapeutic opportunities. ACTA ACUST UNITED AC 2020; 18:425-432. [PMID: 32523869 DOI: 10.1007/s11901-019-00495-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Purpose of review In this review article we evaluate sex differences in the natural history of NAFLD and highlight distinct risk profiles of women with NAFLD, as well as unique treatment considerations and research gaps. Summary of findings Reproductive factors, such as menopausal status should be considered when evaluating NAFLD risk in women, as well as additional reproductive risk factors such as age at menarche, presence of polycystic ovary syndrome, and gestational diabetes. Women do appear to have lower risk for hepatocellular carcinoma from NASH, as well as lower mortality from NASH cirrhosis than men, although among women, NASH is now the leading indication for liver transplant. Data on sex differences in biomarker development and clinical trials are lacking, and researchers should be encouraged to evaluate biomarker performance by sex, and specifically report clinical trial endpoints in women.
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Affiliation(s)
- Liyun Yuan
- University of Southern California, Division of GI/Hepatology
| | - Ani Kardashian
- University of California, San Francisco, Division of GI/Hepatology
| | - Monika Sarkar
- University of California, San Francisco, Division of GI/Hepatology
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