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Talari NK, Mattam U, Rahman AP, Hemmelgarn BK, Wyder MA, Sylvestre PB, Greis KD, Chella Krishnan K. Functional compartmentalization of hepatic mitochondrial subpopulations during MASH progression. Commun Biol 2025; 8:258. [PMID: 39966593 PMCID: PMC11836293 DOI: 10.1038/s42003-025-07713-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 02/11/2025] [Indexed: 02/20/2025] Open
Abstract
The role of peridroplet mitochondria (PDM) in diseased liver, such as during the progression of metabolic dysfunction-associated steatohepatitis (MASH), remains unknown. We isolated hepatic cytoplasmic mitochondria (CM) and PDM from a mouse model of diet-induced MASLD/MASH to characterize their functions from simple steatosis to advanced MASH, using chow-fed mice as controls. Our findings show an inverse relationship between hepatic CM and PDM levels from healthy to steatosis to advanced MASH. Proteomics analysis revealed these two mitochondrial populations are compositionally and functionally distinct. We found that hepatic PDM are more bioenergetically active than CM, with higher pyruvate oxidation capacity in both healthy and diseased liver. Higher respiration capacity of PDM was associated with elevated OXPHOS protein complexes and increased TCA cycle flux. In contrast, CM showed higher fatty acid oxidation capacity with MASH progression. Transmission electron microscopy revealed larger and elongated mitochondria during healthy and early steatosis, which appeared small and fragmented during MASH progression. These changes coincided with higher MFN2 protein levels in hepatic PDM and higher DRP1 protein levels in hepatic CM. These findings highlight the distinct roles of hepatic CM and PDM in MASLD progression towards MASH.
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Affiliation(s)
- Noble Kumar Talari
- Department of Pharmacology, Physiology, and Neurobiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Ushodaya Mattam
- Department of Pharmacology, Physiology, and Neurobiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Afra P Rahman
- Medical Sciences Baccalaureate Program, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Brook K Hemmelgarn
- Department of Pharmacology, Physiology, and Neurobiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Michael A Wyder
- Department of Cancer Biology, Proteomics Laboratory, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Pamela B Sylvestre
- Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Kenneth D Greis
- Department of Cancer Biology, Proteomics Laboratory, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Karthickeyan Chella Krishnan
- Department of Pharmacology, Physiology, and Neurobiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
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Ohshima K, Hara E, Takimoto M, Bai Y, Hirata M, Zeng W, Uomoto S, Todoroki M, Kobayashi M, Kozono T, Kigata T, Shibutani M, Yoshida T. Peroxisome Proliferator Activator α Agonist Clofibrate Induces Pexophagy in Coconut Oil-Based High-Fat Diet-Fed Rats. BIOLOGY 2024; 13:1027. [PMID: 39765694 PMCID: PMC11673738 DOI: 10.3390/biology13121027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 12/04/2024] [Accepted: 12/05/2024] [Indexed: 01/03/2025]
Abstract
Peroxisomes are crucial for fatty acid β-oxidation in steatosis, but the role of pexophagy-the selective autophagy of peroxisomes-remains unclear. This study investigated the effects of the peroxisome proliferator-activated receptor-α (PPARα) agonist clofibrate on pexophagy in a coconut oil-based high-fat diet (HFD)-induced hepatocarcinogenesis model. Rats were divided into four groups: control, clofibrate, HFD, and HFD with clofibrate. The HFD induced steatosis, along with a 2.4-fold increase in pexophagy receptor NBR1-positive granules in hepatocytes. Clofibrate significantly inhibited HFD-induced steatosis, increasing p62-, LAMP2-, and Pex5-positive granules by 7.5-, 7.2-, and 71.4-fold, respectively, while decreasing NBR1 expression. The effects were associated with peroxisome proliferation and pexophagy in ultrastructural observations and increased levels of Lc3, p62, Pex2, Pex14, Acox1, and Scd1 in gene expression analysis. The results suggested that clofibrate effectively reduced steatosis through combined peroxisome proliferation and pexophagy, though it had a marginal impact on hepatocarcinogenesis in coconut oil-based HFD-fed rats. These findings highlight the utility of PPARα agonists in studying mammalian pexophagy.
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Affiliation(s)
- Kanami Ohshima
- Laboratory of Veterinary Pathology, Cooperative Department of Veterinary Medicine, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Tokyo 183-8509, Japan (M.S.)
| | - Emika Hara
- Laboratory of Veterinary Pathology, Cooperative Department of Veterinary Medicine, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Tokyo 183-8509, Japan (M.S.)
| | - Mio Takimoto
- Laboratory of Veterinary Pathology, Cooperative Department of Veterinary Medicine, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Tokyo 183-8509, Japan (M.S.)
| | - Yidan Bai
- Laboratory of Veterinary Pathology, Cooperative Department of Veterinary Medicine, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Tokyo 183-8509, Japan (M.S.)
| | - Mai Hirata
- Laboratory of Veterinary Pathology, Cooperative Department of Veterinary Medicine, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Tokyo 183-8509, Japan (M.S.)
| | - Wen Zeng
- Laboratory of Veterinary Pathology, Cooperative Department of Veterinary Medicine, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Tokyo 183-8509, Japan (M.S.)
| | - Suzuka Uomoto
- Laboratory of Veterinary Pathology, Cooperative Department of Veterinary Medicine, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Tokyo 183-8509, Japan (M.S.)
| | - Mai Todoroki
- Laboratory of Veterinary Pathology, Cooperative Department of Veterinary Medicine, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Tokyo 183-8509, Japan (M.S.)
- Cooperative Division of Veterinary Sciences, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Tokyo 183-8509, Japan
| | - Mio Kobayashi
- Laboratory of Veterinary Pathology, Cooperative Department of Veterinary Medicine, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Tokyo 183-8509, Japan (M.S.)
- Cooperative Division of Veterinary Sciences, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Tokyo 183-8509, Japan
| | - Takuma Kozono
- Smart-Core-Facility Promotion Organization, 3-5-8 Saiwai-cho, Tokyo 183-8509, Japan;
| | - Tetsuhito Kigata
- Laboratory of Veterinary Anatomy, Cooperative Department of Veterinary Medicine, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Tokyo 183-8509, Japan;
| | - Makoto Shibutani
- Laboratory of Veterinary Pathology, Cooperative Department of Veterinary Medicine, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Tokyo 183-8509, Japan (M.S.)
| | - Toshinori Yoshida
- Laboratory of Veterinary Pathology, Cooperative Department of Veterinary Medicine, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Tokyo 183-8509, Japan (M.S.)
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Ruppert Z, Neuperger P, Rákóczi B, Gémes N, Dukay B, Hajdu P, Péter M, Balogh G, Tiszlavicz L, Vígh L, Török Z, Puskás LG, Szebeni GJ, Tóth ME. Characterization of obesity-related diseases and inflammation using single cell immunophenotyping in two different diet-induced obesity models. Int J Obes (Lond) 2024; 48:1568-1576. [PMID: 39004641 PMCID: PMC11502477 DOI: 10.1038/s41366-024-01584-6] [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: 01/18/2024] [Revised: 07/04/2024] [Accepted: 07/05/2024] [Indexed: 07/16/2024]
Abstract
BACKGROUND Obesity is a growing problem worldwide and a major risk factor for many chronic diseases. The accumulation of adipose tissue leads to the release of significant amounts of pro-inflammatory cytokines and adipokines, resulting in a low-grade systemic inflammation. However, the mechanisms behind the development of obesity-related diseases are not fully understood. Therefore, our study aimed to investigate the pathological changes and inflammatory processes at systemic level and in individual organs in two different diet-induced mouse obesity models. METHODS Male C57BL6/J mice were fed by high-fat diet (HFD), high-fat/high-fructose diet (HFD + FR) or normal chow for 21 weeks starting at 3 months of age (n = 15 animals/group). Insulin resistance was tested by oral glucose tolerance test. Pathological changes were investigated on hematoxylin-eosin-stained liver and brown adipose tissue sections. The gene expression levels of adipokines and cytokines were analyzed by qPCR in adipose tissues, whereas serum protein concentrations were determined by multiplex immunoassays. Immunophenotyping of isolated blood, bone marrow and spleen cells was performed by single-cell mass cytometry. RESULTS Weight gain, glucose intolerance and hepatic steatosis were more severe in the HFD + FR group than in the control and HFD groups. This was accompanied by a higher level of systemic inflammation, as indicated by increased expression of pro-inflammatory genes in visceral white adipose tissue and by a higher serum TNFα level. In addition, immunophenotyping revealed the increase of the surface expressions of CD44 and CD69 on various cell types, such as CD8+ and CD4 + T-cells, B-cells and macrophages, in animals with obesity. CONCLUSIONS The combination of HFD with fructose supplementation promotes more properly the symptoms of metabolic syndrome. Therefore, the combined high-fat/high-fructose nutrition can be a more suitable model of the Western diet. However, despite these differences, both models showed immunophenotypic changes that may be associated with increased risk of obesity-related cancer.
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Affiliation(s)
- Zsófia Ruppert
- Laboratory of Molecular Stress Biology, Institute of Biochemistry, HUN-REN Biological Research Centre, Szeged, Hungary
- PhD School in Biology, University of Szeged, Szeged, Hungary
| | - Patrícia Neuperger
- PhD School in Biology, University of Szeged, Szeged, Hungary
- Laboratory of Functional Genomics, Core Facility, HUN-REN Biological Research Centre, Szeged, Hungary
| | - Bettina Rákóczi
- Laboratory of Molecular Stress Biology, Institute of Biochemistry, HUN-REN Biological Research Centre, Szeged, Hungary
- PhD School in Biology, University of Szeged, Szeged, Hungary
| | - Nikolett Gémes
- PhD School in Biology, University of Szeged, Szeged, Hungary
- Laboratory of Functional Genomics, Core Facility, HUN-REN Biological Research Centre, Szeged, Hungary
| | - Brigitta Dukay
- Laboratory of Molecular Stress Biology, Institute of Biochemistry, HUN-REN Biological Research Centre, Szeged, Hungary
| | - Petra Hajdu
- Laboratory of Molecular Stress Biology, Institute of Biochemistry, HUN-REN Biological Research Centre, Szeged, Hungary
| | - Mária Péter
- Laboratory of Molecular Stress Biology, Institute of Biochemistry, HUN-REN Biological Research Centre, Szeged, Hungary
| | - Gábor Balogh
- Laboratory of Molecular Stress Biology, Institute of Biochemistry, HUN-REN Biological Research Centre, Szeged, Hungary
| | - László Tiszlavicz
- Department of Pathology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
| | - László Vígh
- Laboratory of Molecular Stress Biology, Institute of Biochemistry, HUN-REN Biological Research Centre, Szeged, Hungary
| | - Zsolt Török
- Laboratory of Molecular Stress Biology, Institute of Biochemistry, HUN-REN Biological Research Centre, Szeged, Hungary
| | - László G Puskás
- Laboratory of Functional Genomics, Core Facility, HUN-REN Biological Research Centre, Szeged, Hungary
| | - Gábor J Szebeni
- Laboratory of Functional Genomics, Core Facility, HUN-REN Biological Research Centre, Szeged, Hungary.
- Department of Internal Medicine, Hematology Centre, Faculty of Medicine, University of Szeged, H6725, Szeged, Hungary.
| | - Melinda E Tóth
- Laboratory of Molecular Stress Biology, Institute of Biochemistry, HUN-REN Biological Research Centre, Szeged, Hungary.
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Talari NK, Mattam U, Kaminska D, Sotomayor-Rodriguez I, Rahman AP, Péterfy M, Pajukanta P, Pihlajamäki J, Chella Krishnan K. Hepatokine ITIH3 protects against hepatic steatosis by downregulating mitochondrial bioenergetics and de novo lipogenesis. iScience 2024; 27:109709. [PMID: 38689636 PMCID: PMC11059128 DOI: 10.1016/j.isci.2024.109709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 02/16/2024] [Accepted: 04/06/2024] [Indexed: 05/02/2024] Open
Abstract
Recent studies demonstrate that liver secretory proteins, also known as hepatokines, regulate normal development, obesity, and simple steatosis to non-alcoholic steatohepatitis (NASH) progression. Using a panel of ∼100 diverse inbred strains of mice and a cohort of bariatric surgery patients, we found that one such hepatokine, inter-trypsin inhibitor heavy chain 3 (ITIH3), was progressively lower in severe non-alcoholic fatty liver disease (NAFLD) disease states highlighting an inverse relationship between Itih3/ITIH3 expression and NAFLD severity. Follow-up animal and cell culture models demonstrated that hepatic ITIH3 overexpression lowered liver triglyceride and lipid droplet accumulation, respectively. Conversely, ITIH3 knockdown in mice increased the liver triglyceride in two independent NAFLD models. Mechanistically, ITIH3 reduced mitochondrial respiration and this, in turn, reduced liver triglycerides, via downregulated de novo lipogenesis. This was accompanied by increased STAT1 signaling and Stat3 expression, both of which are known to protect against NAFLD/NASH. Our findings indicate hepatokine ITIH3 as a potential biomarker and/or treatment for NAFLD.
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Affiliation(s)
- Noble Kumar Talari
- Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Ushodaya Mattam
- Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Dorota Kaminska
- Department of Medicine, Division of Cardiology, University of California Los Angeles, Los Angeles, CA, USA
- Institute of Public Health and Clinical Nutrition, Department of Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Irene Sotomayor-Rodriguez
- Medical Sciences Baccalaureate Program, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Afra P. Rahman
- Medical Sciences Baccalaureate Program, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Miklós Péterfy
- Department of Basic Medical Sciences, Western University of Health Sciences, Pomona, CA, USA
| | - Päivi Pajukanta
- Department of Human Genetics, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, USA
- Institute for Precision Health, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, USA
| | - Jussi Pihlajamäki
- Institute of Public Health and Clinical Nutrition, Department of Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
- Department of Medicine, Endocrinology and Clinical Nutrition, Kuopio University Hospital, Kuopio, Finland
| | - Karthickeyan Chella Krishnan
- Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
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Shinde S, Taylor N, Chinthammit C, Wilson R, Burgess SM, Poon JL. Understanding the impact of non-alcoholic steatohepatitis with metabolic comorbidities on adults: a real-world qualitative study. Curr Med Res Opin 2024; 40:665-676. [PMID: 38363353 DOI: 10.1080/03007995.2024.2319820] [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: 10/09/2023] [Accepted: 02/13/2024] [Indexed: 02/17/2024]
Abstract
OBJECTIVE Limited real-world evidence exists to better understand the patient experience of living with symptoms and impacts of non-alcoholic steatohepatitis (NASH). This study aimed to (1) describe patient-reported perspectives of NASH symptoms and impacts on patients' daily lives and (2) develop a patient-centered conceptual NASH model. METHODS A cross-sectional study using semi-structured qualitative interviews was conducted among adults (≥18 years) in the United States living with NASH. Eligible participants were diagnosed with NASH, had mild to advanced fibrosis (F1-F3), and no other causes of liver disease. The interview guide was informed by a targeted literature review (TLR) to identify clinical signs, symptoms, impacts, and unmet treatment needs of NASH. Participants described their experiences and perspectives around NASH and the symptoms, symptom severity/bother, and impact of NASH on their daily activities. Interviews were audio-recorded and transcribed verbatim for coding and thematic analysis. RESULTS Twenty participants (age: 42.4 years; female: 50.0%) were interviewed. Participants discussed their experience with NASH symptoms (most frequent: fatigue [75.0%]; weakness/lethargy [70.0%]) and impacts (most frequent: physical and psychological/emotional [70.0% each]; dietary [68.4%]). Participants considered most symptoms to be moderately severe or severe and moderately or highly bothersome. Findings from the TLR and qualitative interviews were incorporated into a conceptual model that describes patient-reported symptoms and impacts of NASH, clinical signs, risk factors, and unmet treatment needs. CONCLUSION Our study provides insights into patients' perspectives of NASH symptoms and their impact on their daily lives. These findings may guide patient-physician conversations, supporting patient-centered treatment decisions and disease management.
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Verma N, Duseja A, Mehta M, De A, Lin H, Wong VWS, Wong GLH, Rajaram RB, Chan WK, Mahadeva S, Zheng MH, Liu WY, Treeprasertsuk S, Prasoppokakorn T, Kakizaki S, Seki Y, Kasama K, Charatcharoenwitthaya P, Sathirawich P, Kulkarni A, Purnomo HD, Kamani L, Lee YY, Wong MS, Tan EXX, Young DY. Machine learning improves the prediction of significant fibrosis in Asian patients with metabolic dysfunction-associated steatotic liver disease - The Gut and Obesity in Asia (GO-ASIA) Study. Aliment Pharmacol Ther 2024; 59:774-788. [PMID: 38303507 DOI: 10.1111/apt.17891] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Revised: 11/28/2023] [Accepted: 01/20/2024] [Indexed: 02/03/2024]
Abstract
BACKGROUND The precise estimation of cases with significant fibrosis (SF) is an unmet goal in non-alcoholic fatty liver disease (NAFLD/MASLD). AIMS We evaluated the performance of machine learning (ML) and non-patented scores for ruling out SF among NAFLD/MASLD patients. METHODS Twenty-one ML models were trained (N = 1153), tested (N = 283), and validated (N = 220) on clinical and biochemical parameters of histologically-proven NAFLD/MASLD patients (N = 1656) collected across 14 centres in 8 Asian countries. Their performance for detecting histological-SF (≥F2fibrosis) were evaluated with APRI, FIB4, NFS, BARD, and SAFE (NPV/F1-score as model-selection criteria). RESULTS Patients aged 47 years (median), 54.6% males, 73.7% with metabolic syndrome, and 32.9% with histological-SF were included in the study. Patients with SFvs.no-SF had higher age, aminotransferases, fasting plasma glucose, metabolic syndrome, uncontrolled diabetes, and NAFLD activity score (p < 0.001, each). ML models showed 7%-12% better discrimination than FIB-4 to detect SF. Optimised random forest (RF) yielded best NPV/F1 in overall set (0.947/0.754), test set (0.798/0.588) and validation set (0.852/0.559), as compared to FIB4 in overall set (0.744/0.499), test set (0.722/0.456), and validation set (0.806/0.507). Compared to FIB-4, RF could pick 10 times more patients with SF, reduce unnecessary referrals by 28%, and prevent missed referrals by 78%. Age, AST, ALT fasting plasma glucose, and platelet count were top features determining the SF. Sequential use of SAFE < 140 and FIB4 < 1.2 (when SAFE > 140) was next best in ruling out SF (NPV of 0.757, 0.724 and 0.827 in overall, test and validation set). CONCLUSIONS ML with clinical, anthropometric data and simple blood investigations perform better than FIB-4 for ruling out SF in biopsy-proven Asian NAFLD/MASLD patients.
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Affiliation(s)
- Nipun Verma
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Ajay Duseja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Manu Mehta
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Arka De
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Huapeng Lin
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
| | - Vincent Wai-Sun Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
| | - Grace Lai-Hung Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
| | - Ruveena Bhavani Rajaram
- Gastroenterology and Hepatology Unit, Department of Medicine, Faculty of Medicine, University of Malaya Medical Centre, Kuala Lumpur, Malaysia
| | - Wah-Kheong Chan
- Gastroenterology and Hepatology Unit, Department of Medicine, Faculty of Medicine, University of Malaya Medical Centre, Kuala Lumpur, Malaysia
| | - Sanjiv Mahadeva
- Gastroenterology and Hepatology Unit, Department of Medicine, Faculty of Medicine, University of Malaya Medical Centre, Kuala Lumpur, Malaysia
| | - Ming-Hua Zheng
- NAFLD Research Centre Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Wen-Yue Liu
- Department of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Sombat Treeprasertsuk
- Division of Gastroenterology, King Chulalongkorn Memorial Hospital, Chulalongkorn University, Bangkok, Thailand
| | - Thaninee Prasoppokakorn
- Division of Gastroenterology, King Chulalongkorn Memorial Hospital, Chulalongkorn University, Bangkok, Thailand
| | - Satoru Kakizaki
- Department of Clinical Research, National Hospital Organization Takasaki General Medical Centre, Takasaki, Japan
| | - Yosuke Seki
- Weight Loss and Metabolic Surgery Centre, Yotsuya Medical Cube, Tokyo, Japan
| | - Kazunori Kasama
- Weight Loss and Metabolic Surgery Centre, Yotsuya Medical Cube, Tokyo, Japan
| | | | - Phalath Sathirawich
- Division of Gastroenterology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Anand Kulkarni
- Asian Institute of Gastroenterology Hospital, Hyderabad, India
| | - Hery Djagat Purnomo
- Faculty of Medicine, Diponegoro University, Kariadi Hospital, Semarang, Indonesia
| | | | - Yeong Yeh Lee
- School of Medical Sciences Universiti Sains Malaysia, Kota Bharu, Malaysia
| | - Mung Seong Wong
- School of Medical Sciences Universiti Sains Malaysia, Kota Bharu, Malaysia
| | - Eunice X X Tan
- Department of Medicine, National University Singapore, Singapore, Singapore
| | - Dan Yock Young
- Department of Medicine, National University Singapore, Singapore, Singapore
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Zaky YA, Rashad MW, Zaater MA, El Kerdawy AM. Discovery of dual rho-associated protein kinase 1 (ROCK1)/apoptosis signal-regulating kinase 1 (ASK1) inhibitors as a novel approach for non-alcoholic steatohepatitis (NASH) treatment. BMC Chem 2024; 18:2. [PMID: 38172941 PMCID: PMC10765837 DOI: 10.1186/s13065-023-01081-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 11/08/2023] [Indexed: 01/05/2024] Open
Abstract
In the current study we suggest a novel approach to curb non-alcoholic steatohepatitis (NASH) progression, and we suggest privileged scaffolds for the design of novel compounds for this aim. NASH is an advanced form of non-alcoholic fatty liver disease that can further progress into fibrosis, cirrhosis, and hepatocellular carcinoma. It is a widely emerging disease affecting 25% of the global population and has no current approved treatments. Protein kinases are key regulators of cellular pathways, of which, Rho-associated protein kinase 1 (ROCK1) and apoptosis signal-regulating kinase 1 (ASK1) play an important role in the progression of NASH and they stand out as promising targets for NASH therapy. Interestingly, their kinase domains are found to be similar in sequence and topology; therefore, dual inhibition of ROCK1 and ASK1 is expected to be amenable and could achieve a more favourable outcome. To reach this goal, a training set of ROCK1 and ASK1 protein structures co-crystalized with type 1 (ATP-competitive) inhibitors was constructed to manually generate receptor-based pharmacophore models representing ROCK1 and ASK1 inhibitors' common pharmacophoric features. The models produced were assessed using a test set of both ROCK1 and ASK1 actives and decoys, and their performance was evaluated using different assessment metrics. The best pharmacophore model obtained, showing a Mathew's correlation coefficient (MCC) of 0.71, was then used to screen the ZINC purchasable database retrieving 6178 hits that were filtered accordingly using several medicinal chemistry and pharmacokinetics filters returning 407 promising compounds. To confirm that these compounds are capable of binding to the target kinases, they were subjected to molecular docking simulations at both protein structures. The results were then assessed individually and filtered, setting the spotlight on various privileged scaffolds that could be exploited as the nucleus for designing novel ROCK1/ASK1 dual inhibitors.
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Affiliation(s)
- Yara A Zaky
- Department of Chemistry, School of Pharmacy, Newgiza University (NGU), Newgiza, Km 22 Cairo-Alexandria Desert Road, Cairo, Egypt.
| | - Mai W Rashad
- Department of Chemistry, School of Pharmacy, Newgiza University (NGU), Newgiza, Km 22 Cairo-Alexandria Desert Road, Cairo, Egypt
| | - Marwa A Zaater
- Master Postgraduate Program, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Ahmed M El Kerdawy
- Department of Chemistry, School of Pharmacy, Newgiza University (NGU), Newgiza, Km 22 Cairo-Alexandria Desert Road, Cairo, Egypt
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
- School of Pharmacy, College of Science, University of Lincoln, Joseph Banks Laboratories, Green Lane, Lincoln, Lincolnshire, UK
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8
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Aoko O, Maharaj T, Boland F, Cheriyan D, Ryan J. Meta-analysis: Impact of intragastric balloon therapy on NAFLD-related parameters in patients with obesity. Aliment Pharmacol Ther 2024; 59:8-22. [PMID: 37986213 DOI: 10.1111/apt.17805] [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: 04/02/2023] [Revised: 10/27/2023] [Accepted: 10/27/2023] [Indexed: 11/22/2023]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease affecting approximately 25% of adults in the western world. Intragastric balloon (IGB) is an endoscopic bariatric therapy -a therapeutic endoscopic tool that has shown promise in inducing weight loss. Its role in the treatment of NAFLD is yet to be established. AIM To evaluate the effect of IGB as a treatment option in NAFLD. METHODS We searched MEDLINE (PubMed) and EMBASE from inception to September 2022. We included studies evaluating the impact of IGB on obesity with the assessment of one or more liver-related outcomes and studies primarily evaluating the impact of IGB on NAFLD. We included comparative and non-comparative studies; primary outcomes were liver-related NAFLD surrogates. RESULTS We included 19 studies with 911 patients. IGB demonstrated an effect on NAFLD parameters including NAFLD activity score (NAS): mean difference (MD): -3.0 [95% CI: -2.41 to -3.59], ALT: MD: -10.40 U/L [95% CI: -7.31 to -13.49], liver volume: MD -397.9 [95% CI: -212.78 to 1008.58] and liver steatosis: MD: -37.76 dB/m [95% CI: -21.59 to -53.92]. There were significant reductions in non-liver-related outcomes of body weight, BMI, glycated haemoglobin and HOMA-IR. CONCLUSION Intragastric balloons may play an important role in addressing the treatment gap in NAFLD management.
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Affiliation(s)
- Olufemi Aoko
- Hepatology Department, Beaumont Hospital, Dublin, Ireland
- Gastroenterology Department, Beaumont Hospital, Dublin, Ireland
| | - Tobias Maharaj
- Hepatology Department, Beaumont Hospital, Dublin, Ireland
- Gastroenterology Department, Beaumont Hospital, Dublin, Ireland
| | - Fiona Boland
- Gastroenterology Department, Beaumont Hospital, Dublin, Ireland
| | | | - John Ryan
- Hepatology Department, Beaumont Hospital, Dublin, Ireland
- Gastroenterology Department, Beaumont Hospital, Dublin, Ireland
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9
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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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10
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Raya-Cano E, Molina-Luque R, Vaquero-Abellán M, Molina-Recio G, Jiménez-Mérida R, Romero-Saldaña M. Metabolic syndrome and transaminases: systematic review and meta-analysis. Diabetol Metab Syndr 2023; 15:220. [PMID: 37899468 PMCID: PMC10614379 DOI: 10.1186/s13098-023-01200-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 10/24/2023] [Indexed: 10/31/2023] Open
Abstract
BACKGROUND Metabolic syndrome (MetS) is a group of metabolic abnormalities characterised by hypertension, central obesity, dyslipidaemia and dysregulation of blood glucose, associated with the risk of diabetes, cardiovascular disease and overall mortality. The presence of elevated liver enzymes may precede the development of MetS, with alterations of the liver being observed that are directly related to metabolic problems. The study aims to provide the best evidence on the association between liver enzymes (ALT, AST, GGT) and MetS by determining the effect size of these biomarkers. METHODS A systematic review and meta-analysis of studies indexed in PubMed and Scopus databases were performed. Study quality was assessed using the STROBE tool. The Grade Pro tool was used to evaluate the evidence, and the quantitative synthesis was performed using RevMan (Cochrane Collaboration). RESULTS Seventeen articles comparing liver enzyme concentrations between 76,686 with MetS (MetS+) and 201,855 without MetS (MetS-) subjects were included. The concentration of ALT, AST and GGT in the MetS + subjects was significantly higher than in the control group 7.13 IU/L (CI95% 5.73-8.54; p < 0.00001; I2 = 96%), 2.68 IU/L (CI95% 1.82-3.54; p < 0.00001; I2 = 96%) and 11.20 IU/L (CI95% 7.11-15.29; p < 0.00001; I2 = 96%), respectively. CONCLUSIONS The evaluation of the relationship of liver enzymes in the pathophysiological process of MetS could lead to new insights into early diagnosis.
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Affiliation(s)
- Elena Raya-Cano
- Faculty of Medicine and Nursing, University of Córdoba, Avd. Menéndez Pidal N/N, Córdoba, 14004, Spain
| | - Rafael Molina-Luque
- Faculty of Medicine and Nursing, University of Córdoba, Avd. Menéndez Pidal N/N, Córdoba, 14004, Spain.
- Lifestyles, Innovation and Health (GA-16), Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain.
| | - Manuel Vaquero-Abellán
- Faculty of Medicine and Nursing, University of Córdoba, Avd. Menéndez Pidal N/N, Córdoba, 14004, Spain
| | - Guillermo Molina-Recio
- Faculty of Medicine and Nursing, University of Córdoba, Avd. Menéndez Pidal N/N, Córdoba, 14004, Spain
- Lifestyles, Innovation and Health (GA-16), Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain
| | - Rocío Jiménez-Mérida
- Faculty of Medicine and Nursing, University of Córdoba, Avd. Menéndez Pidal N/N, Córdoba, 14004, Spain
| | - Manuel Romero-Saldaña
- Faculty of Medicine and Nursing, University of Córdoba, Avd. Menéndez Pidal N/N, Córdoba, 14004, Spain
- Lifestyles, Innovation and Health (GA-16), Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain
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11
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Amjad W, Shalaurova I, Garcia E, Gruppen EG, Dullaart RPF, DePaoli AM, Jiang ZG, Lai M, Connelly MA. Circulating Citrate Is Associated with Liver Fibrosis in Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis. Int J Mol Sci 2023; 24:13332. [PMID: 37686138 PMCID: PMC10487511 DOI: 10.3390/ijms241713332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 08/21/2023] [Accepted: 08/24/2023] [Indexed: 09/10/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is associated with mitochondrial damage. Circulating mitochondrial metabolites may be elevated in NAFLD but their associations with liver damage is not known. This study aimed to assess the association of key mitochondrial metabolites with the degree of liver fibrosis in the context of NAFLD and nonalcoholic steatohepatitis (NASH). Cross-sectional analyses were performed on two cohorts of biopsy-proven NAFLD and/or NASH subjects. The association of circulating mitochondrial metabolite concentrations with liver fibrosis was assessed using linear regression analysis. In the single-center cohort of NAFLD subjects (n = 187), the mean age was 54.9 ±13.0 years, 40.1% were female and 86.1% were White. Type 2 diabetes (51.3%), hypertension (43.9%) and obesity (72.2%) were prevalent. Those with high citrate had a higher proportion of moderate/significant liver fibrosis (stage F ≥ 2) (68.4 vs. 39.6%, p = 0.001) and advanced fibrosis (stage F ≥ 3) (31.6 vs. 13.6%, p = 0.01). Citrate was associated with liver fibrosis independent of age, sex, NAFLD activity score and metabolic syndrome (per 1 SD increase: β = 0.19, 95% CI: 0.03-0.35, p = 0.02). This association was also observed in a cohort of NASH subjects (n = 176) (β = 0.21, 95% CI: 0.07-0.36, p = 0.005). The association of citrate with liver fibrosis was observed in males (p = 0.005) but not females (p = 0.41). In conclusion, circulating citrate is elevated and associated with liver fibrosis, particularly in male subjects with NAFLD and NASH. Mitochondrial function may be a target to consider for reducing the progression of liver fibrosis and NASH.
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Affiliation(s)
- Waseem Amjad
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School, Boston, MA 02215, USA; (W.A.); (Z.G.J.); (M.L.)
| | | | - Erwin Garcia
- Labcorp, Morrisville, NC 27560, USA; (I.S.); (E.G.)
| | - Eke G. Gruppen
- Divisions of Nephrology and Endocrinology, University Medical Center Groningen (UMCG), University of Groningen, 9713 Groningen, The Netherlands; (E.G.G.); (R.P.F.D.)
| | - Robin P. F. Dullaart
- Divisions of Nephrology and Endocrinology, University Medical Center Groningen (UMCG), University of Groningen, 9713 Groningen, The Netherlands; (E.G.G.); (R.P.F.D.)
| | | | - Z. Gordon Jiang
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School, Boston, MA 02215, USA; (W.A.); (Z.G.J.); (M.L.)
| | - Michelle Lai
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School, Boston, MA 02215, USA; (W.A.); (Z.G.J.); (M.L.)
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12
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Zhao Y, Sun N, Song X, Zhu J, Wang T, Wang Z, Yu Y, Ren J, Chen H, Zhan T, Tian J, Ma C, Huang J, Wang J, Zhang Y, Yang B. A novel small molecule AdipoR2 agonist ameliorates experimental hepatic steatosis in hamsters and mice. Free Radic Biol Med 2023; 203:69-85. [PMID: 37044149 DOI: 10.1016/j.freeradbiomed.2023.04.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 04/02/2023] [Indexed: 04/14/2023]
Abstract
Adiponectin receptor 2 (AdipoR2) can be activated by its endogenous ligand adiponectin to reduce hepatic steatosis, and is regarded as a therapeutic target for metabolic associated fatty liver disease (MAFLD). This study proposes a novel anthraquinone compound, emodin succinate monoethyl ester (ESME), which activates AdipoR2, inhibits hepatic lipogenesis, promotes fatty acid oxidation, and alleviates experimental hepatic steatosis in hamsters and mice. Molecular docking shows that ESME has strong binding potential with AdipoR2 by forming a arene-arene interaction. AdipoR2 on the cytomembrane of HepG2 cells can be labeled by fluorescent ESME (Cy5-ESME). ESME activates AdipoR2, AMPK and PPARα, and reduces lipid deposition in palmitic acid or oleic acid-induced HepG2 and L02 cells. Suppression of AdipoR2 expression or AMPK activation completely eliminates the effect of ESME on reducing lipid accumulation in hepatocytes. Oral administration of ESME reduces liver lipid production and accumulation, and alleviates hepatic steatosis in hamsters and Apoe-/- mice induced by high-fat diet. Compared with statins and emodin, ESME showed prepotent efficacy and safety in reducing hepatic steatosis and protecting hepatocytes. Furthermore, ESME activates CaMKK2 and LKB1 in liver to activate AMPK and reduce lipogenesis through stimulating AdipoR2. Taken together, ESME reduces hepatic lipid accumulation and alleviates hepatic steatosis by agonizing AdipoR2. ESME is a promising new agent for clinical treatment of MAFLD.
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Affiliation(s)
- Yixiu Zhao
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Na Sun
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Xia Song
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Jia Zhu
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Tianshuo Wang
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Zhiqi Wang
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Yuanyuan Yu
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Jing Ren
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Huan Chen
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Tingting Zhan
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Jiaying Tian
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Chunyue Ma
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Jian Huang
- Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, Harbin Medical University, Harbin, China
| | - Jinhui Wang
- Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, Harbin Medical University, Harbin, China
| | - Yan Zhang
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China.
| | - Baofeng Yang
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China.
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13
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Park J, Kim G, Kim H, Lee J, Jin SM, Kim JH. The associations between changes in hepatic steatosis and heart failure and mortality: a nationwide cohort study. Cardiovasc Diabetol 2022; 21:287. [PMID: 36564787 PMCID: PMC9789584 DOI: 10.1186/s12933-022-01725-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 12/12/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a well-known risk factor for cardiovascular (CV) disease (CVD) and mortality. However, whether the progression or regression of NAFLD can increase or decrease the risk of heart failure (HF) and mortality has not been fully evaluated. We investigated the association between changes in hepatic steatosis and the risks of incident HF (iHF), hospitalization for HF (hHF), and mortality including CV- or liver-related mortality. METHODS Using a database from the National Health Insurance Service in Korea from January 2009 to December 2012, we analyzed 240,301 individuals who underwent health check-ups at least twice in two years. Hepatic steatosis was assessed using the fatty liver index (FLI), with an FLI ≥ 60 considered to indicate the presence of hepatic steatosis. According to FLI changes, participants were divided into four groups. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using multivariable Cox proportional hazards regression models. RESULTS Persistent hepatic steatosis increased the risk of iHF, hHF, and mortality including CV- and liver-related mortality compared with the group that never had steatosis (all P < 0.05). Incident hepatic steatosis was associated with increased risk for iHF and mortality including CV- or liver-related mortality (all P < 0.05). Compared with persistent steatosis, regression of hepatic steatosis was associated with decreased risk for iHF, hHF, and liver-related mortality (iHF, HR [95% CI], 0.800 [0.691-0.925]; hHF, 0.645 [0.514-0.810]; liver-related mortality, 0.434 [0.223-0.846]). CONCLUSIONS FLI changes were associated with increased or decreased risk of HF outcomes and mortality.
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Affiliation(s)
- Jiyun Park
- grid.410886.30000 0004 0647 3511Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, 13496 Republic of Korea ,grid.264381.a0000 0001 2181 989XSungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Gyuri Kim
- grid.264381.a0000 0001 2181 989XDepartment of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81, Irwon-Ro, Gangnam-Gu, Seoul, 06351 Republic of Korea
| | - Hasung Kim
- grid.488317.10000 0004 0626 1869Data Science Team, Hanmi Pharm. Co. Ltd, Seoul, Republic of Korea
| | - Jungkuk Lee
- grid.488317.10000 0004 0626 1869Data Science Team, Hanmi Pharm. Co. Ltd, Seoul, Republic of Korea
| | - Sang-Man Jin
- grid.264381.a0000 0001 2181 989XDepartment of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81, Irwon-Ro, Gangnam-Gu, Seoul, 06351 Republic of Korea
| | - Jae Hyeon Kim
- grid.264381.a0000 0001 2181 989XDepartment of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81, Irwon-Ro, Gangnam-Gu, Seoul, 06351 Republic of Korea ,Department of Clinical Research Design and Evaluation, Samsung Advanced Institute for Health Sciences and Technology, Seoul, Republic of Korea
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14
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Abdulali AA, Murad SK, Shahid RA. Clinical Study of Serum Gamma- Glutamyl Levels in Cigarette Smokers with Nonalcoholic Fatty Liver Disease, Governorate – Iraq. 2022 INTERNATIONAL SYMPOSIUM ON MULTIDISCIPLINARY STUDIES AND INNOVATIVE TECHNOLOGIES (ISMSIT) 2022:176-181. [DOI: 10.1109/ismsit56059.2022.9932771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Affiliation(s)
| | - Sarah Kadhim Murad
- College of Health and Medical Technology, Al-Ayen University,Thi-Qar,Iraq
| | - Rola Ali Shahid
- College of Health and Medical Technology, Al-Ayen University,Thi-Qar,Iraq
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15
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Balkrishna A, Gohel V, Kumari P, Manik M, Bhattacharya K, Dev R, Varshney A. Livogrit Prevents Methionine-Cystine Deficiency Induced Nonalcoholic Steatohepatitis by Modulation of Steatosis and Oxidative Stress in Human Hepatocyte-Derived Spheroid and in Primary Rat Hepatocytes. Bioengineered 2022; 13:10811-10826. [PMID: 35485140 PMCID: PMC9208489 DOI: 10.1080/21655979.2022.2065789] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
The prevalence of nonalcoholic steatohepatitis (NASH), characterized by fatty liver, oxidative injury, and inflammation, has considerably increased in the recent years. Due to the complexity of NASH pathogenesis, compounds which can target different mechanisms and stages of NASH development are required. A robust screening model with translational capability is also required to develop therapies targeting NASH. In this study, we used HepG2 spheroids and rat primary hepatocytes to evaluate the potency of Livogrit, a tri-herbal Ayurvedic prescription medicine, as a hepatoprotective agent. NASH was developed in the cells via methionine and cystine-deficient cell culture media. Livogrit at concentration of 30 µg/mL was able to prevent NASH development by decreasing lipid accumulation, ROS production, AST release, NFκB activation and increasing lipolysis, GSH (reduced glutathione), and mitochondrial membrane potential. This study suggests that Livogrit might reduce the lipotoxicity-mediated ROS generation and subsequent production of inflammatory mediators as evident from the increased gene expression of FXR, FGF21, CHOP, CXCL5, and their normalization due to Livogrit treatment. Taken together, Livogrit showed the potential as a multimodal therapeutic formulation capable of attenuating the development of NASH. Our study highlights the potential of Livogrit as a hepatoprotective agent with translational possibilities.
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Affiliation(s)
- Acharya Balkrishna
- Drug Discovery and Development Division, Patanjali Research Institute, Governed by Patanjali Research Foundation Trust, Haridwar, India.,Department of Allied and Applied Sciences, University of Patanjali, Patanjali Yog Peeth, Haridwar, India.,Patanjali Yog Peeth (UK) Trust, Glasgow, UK
| | - Vivek Gohel
- Drug Discovery and Development Division, Patanjali Research Institute, Governed by Patanjali Research Foundation Trust, Haridwar, India
| | - Priya Kumari
- Drug Discovery and Development Division, Patanjali Research Institute, Governed by Patanjali Research Foundation Trust, Haridwar, India
| | - Moumita Manik
- Drug Discovery and Development Division, Patanjali Research Institute, Governed by Patanjali Research Foundation Trust, Haridwar, India
| | - Kunal Bhattacharya
- Drug Discovery and Development Division, Patanjali Research Institute, Governed by Patanjali Research Foundation Trust, Haridwar, India
| | - Rishabh Dev
- Drug Discovery and Development Division, Patanjali Research Institute, Governed by Patanjali Research Foundation Trust, Haridwar, India
| | - Anurag Varshney
- Drug Discovery and Development Division, Patanjali Research Institute, Governed by Patanjali Research Foundation Trust, Haridwar, India.,Department of Allied and Applied Sciences, University of Patanjali, Patanjali Yog Peeth, Haridwar, India.,Special Centre for Systems Medicine, Jawaharlal Nehru University, New Delhi, India
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16
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Shen Y, Zhou Q, Li W, Yuan L. Advances in Optical Imaging of Nonalcoholic Fatty Liver Disease. Chem Asian J 2022; 17:e202200320. [PMID: 35420707 DOI: 10.1002/asia.202200320] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 04/13/2022] [Indexed: 01/10/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD), emerging as one of the most common chronic liver diseases including simple steatosis and non-alcoholic steatohepatitis (NASH), is likely to progress to liver fibrosis and hepatic carcinoma if not treated in time. Therefore, early diagnosis and treatment of NAFLD are necessary. Currently, liver biopsy, as the gold standard for clinical diagnosis of NAFLD, is not widely accepted by patients due to its invasiveness. However, other non-invasive methods that had been reported for NAFLD (such as magnetic resonance imaging, positron emission tomography, and ultrasound) still suffer from low resolution and sensitivity, which are available as a guide for liver biopsy sometimes. As a non-invasive modality with high spatiotemporal resolution and superior sensitivity, optical imaging methods have been widely favored in recent years, mainly including fluorescence imaging, photoacoustic imaging, and bioluminescence imaging. With these optical imaging approaches, a series of optical probes based on optical and molecular-specific design have been developed for the biomarker diagnosis and research of diseases. In this review, we summarize the existing non-invasive optical imaging probes for the detection of biomarkers in NAFLD, including microenvironment (viscosity, polarity), ROS, RSS, ions, proteins, and nucleic acids. Design strategies for optical imaging probes and their applications in NAFLD bioimaging are discussed and focused on. We also highlight the potential challenges and prospects of designing new generations of optical imaging probes in NAFLD studies, which will further enhance the diversity, practicality, and clinical feasibility of NAFLD research.
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Affiliation(s)
| | | | - Wei Li
- Hunan University, chemistry, CHINA
| | - Lin Yuan
- Hunan University, College of Chemistry and Chemical Engineering, NO372, Lushan Rd. Yuelu District., 410082, Changsha, CHINA
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17
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Singh SP, Anirvan P, Khandelwal R, Satapathy SK. Nonalcoholic Fatty Liver Disease (NAFLD) Name Change: Requiem or Reveille? J Clin Transl Hepatol 2021; 9:931-938. [PMID: 34966656 PMCID: PMC8666378 DOI: 10.14218/jcth.2021.00174] [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: 05/10/2021] [Revised: 06/21/2021] [Accepted: 07/18/2021] [Indexed: 12/04/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) affects about a quarter of the world's population and poses a major health and economic burden globally. Recently, there have been hasty attempts to rename NAFLD to metabolic-associated fatty liver disease (MAFLD) despite the fact that there is no scientific rationale for this. Quest for a "positive criterion" to diagnose the disease and destigmatizing the disease have been the main reasons put forth for the name change. A close scrutiny of the pathogenesis of NAFLD would make it clear that NAFLD is a heterogeneous disorder, involving different pathogenic mechanisms of which metabolic dysfunction-driven hepatic steatosis is only one. Replacing NAFLD with MAFLD would neither enhance the legitimacy of clinical practice and clinical trials, nor improve clinical care or move NAFLD research forward. Rather than changing the nomenclature without a strong scientific backing to support such a change, efforts should be directed at understanding NAFLD pathogenesis across diverse populations and ethnicities which could potentially help develop newer therapeutic options.
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Affiliation(s)
- Shivaram P. Singh
- Department of Gastroenterology, Sriram Chandra Bhanj Medical College, Cuttack, Odisha, India
- Correspondence to: Shivaram P Singh, Department of Gastroenterology, Sriram Chandra Bhanj Medical College, Cuttack, Odisha 753007, India. ORCID: https://orcid.org/0000-0002-8197-2674. Tel: +91-9437578857, Fax: +91-671-2433865, E-mail:
| | - Prajna Anirvan
- Department of Gastroenterology, Sriram Chandra Bhanj Medical College, Cuttack, Odisha, India
| | - Reshu Khandelwal
- Department of Gastroenterology, Sriram Chandra Bhanj Medical College, Cuttack, Odisha, India
| | - Sanjaya K. Satapathy
- Division of Hepatology, Sandra Atlas Bass Center for Liver Diseases and Transplantation, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, Manhasset, NY, USA
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Amernia B, Moosavy SH, Banookh F, Zoghi G. FIB-4, APRI, and AST/ALT ratio compared to FibroScan for the assessment of hepatic fibrosis in patients with non-alcoholic fatty liver disease in Bandar Abbas, Iran. BMC Gastroenterol 2021; 21:453. [PMID: 34861841 PMCID: PMC8642865 DOI: 10.1186/s12876-021-02038-3] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 11/22/2021] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. Researchers have tried to develop indices to assess liver fibrosis in NAFLD patients to avoid liver biopsy. In this study we aimed to compare fibrosis-4 (FIB-4), aspartate aminotransferase (AST) to platelet ratio index (APRI), and aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio with FibroScan for the assessment of hepatic fibrosis in patients with NAFLD. METHODS This cross-sectional study included patients with NAFLD or non-alcoholic steatohepatitis (NASH) referred to the Gastroenterology Clinic of Shahid Mohammadi Hospital, Bandar Abbas, Iran, in 2019. Demographic features of the participants including age and gender were recorded. All participants underwent FibroScan and had their AST, ALT, and platelet count measured in a random blood sample, taken within 1 month of the FibroScan. RESULTS Of the 205 NAFLD patients included in this study with a mean age of 42.95 ± 10.97 years, 144 (70.2%) were male. Fibroscan results revealed that 94 patients (45.9%) had F1, 67 (32.7%) F2, 29 (14.1%) F3, and 15 (7.3%) F4 liver fibrosis. A significant correlation was found between FibroScan score and FIB-4 (r = 0.572), APRI (r = 0.667), and AST/ALT (r = 0.251) (P < 0.001). Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of APRI at the 0.702 cut-off for the differentiation of F3 and F4 from F2 and F1 were 84.1, 88.2, 66.1, 95.3, and 87.3%, FIB-4 at the 1.19 cut-off 97.7, 72.7, 49.4, 99.2 and 78%, and AST/ALT at the 0.94 cut-off 61.4, 77, 42.2, 87.9, and 73.7% respectively. Moreover, the area under the receiver operating curve of APRI, FIB-4, and AST/ALT for the differentiation of F3 and F4 from F2 and F1 was 0.923, 0.913, and 0.720, respectively. CONCLUSIONS Based on these results, APRI appears to be the most appropriate substitute of FibroScan for the detection of significant fibrosis in NAFLD patients. FIB-4 was the second best, suggesting that in case of FibroScan unavailability, APRI and FIB-4 are the best indices to assess liver fibrosis in NAFLD patients.
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Affiliation(s)
- Behnaz Amernia
- Department of Gastroenterology, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran.
| | - Seyed Hamid Moosavy
- Department of Gastroenterology, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Fatemeh Banookh
- Student Research Committee, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Ghazal Zoghi
- Endocrinology and Metabolism Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
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19
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Hui ST, Wang F, Stappenbeck F, French SW, Magyar CE, Parhami F, Lusis AJ. Oxy210, a novel inhibitor of hedgehog and TGF-β signalling, ameliorates hepatic fibrosis and hypercholesterolemia in mice. ENDOCRINOLOGY DIABETES & METABOLISM 2021; 4:e00296. [PMID: 34505423 PMCID: PMC8502222 DOI: 10.1002/edm2.296] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 08/02/2021] [Accepted: 08/07/2021] [Indexed: 12/19/2022]
Abstract
AIMS Non-alcoholic steatohepatitis (NASH) is associated with increased overall morbidity and mortality in non-alcoholic fatty liver disease (NAFLD) patients. Liver fibrosis is the strongest prognostic factor for clinical outcomes, liver-related mortality and liver transplantation. Currently, no single therapy or medication for NASH has been approved by the U.S. Food and Drug Administration (FDA). Oxy210, an oxysterol derivative, displays the unique property of antagonizing both Hedgehog (Hh) and transforming growth factor-beta (TGF-β) signalling in primary human hepatic stellate cells (HSC). We hypothesized that inhibition of both Hh and TGF-β signalling by Oxy210 could reduce hepatic fibrosis in NASH. In this study, we examined the therapeutic potential of Oxy210 on NASH in vivo. METHODS We examined the effect of Oxy210 treatment on Hh and TGF-β pathways in HSC. The efficacy of Oxy210 on liver fibrosis was tested in a 'humanized' hyperlipidemic mouse model of NASH that has high relevance to human pathology. APPROACH AND RESULTS We show that Oxy210 inhibits both Hh and TGF-β pathways in human HSC and attenuates baseline and TGF-β-induced expression of pro-fibrotic genes in vitro. Oral delivery of Oxy210 in food resulted in significant liver exposure and significantly reduced hepatic fibrosis in mice over the course of the 16-week study with no apparent safety issues. Additionally, we observed several benefits related to NASH phenotype: (a) reduced plasma pro-inflammatory cytokine and the corresponding hepatic gene expression; (b) reduced pro-fibrotic cytokine and inflammasome gene expression in the liver; (c) reduced apoptosis in the liver; (d) reduced hepatic unesterified cholesterol accumulation; and (e) reduced plasma total and unesterified cholesterol levels. CONCLUSIONS Oxy210 effectively ameliorated hepatic fibrosis and inflammation and improved hypercholesterolemia in mice. Our findings suggest that Oxy210 and related analogues are a new class of drug candidates that may serve as potential therapeutics candidates for NASH.
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Affiliation(s)
- Simon T Hui
- Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, California, USA
| | - Feng Wang
- MAX BioPharma, Inc, Santa Monica, California, USA
| | | | - Samuel W French
- Department of Pathology & Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, USA
| | - Clara E Magyar
- Department of Pathology & Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, USA
| | | | - Aldons J Lusis
- Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, California, USA
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20
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Diet-Regulating Microbiota and Host Immune System in Liver Disease. Int J Mol Sci 2021; 22:ijms22126326. [PMID: 34199182 PMCID: PMC8231888 DOI: 10.3390/ijms22126326] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 06/07/2021] [Accepted: 06/10/2021] [Indexed: 02/07/2023] Open
Abstract
The gut microbiota has been known to modulate the immune responses in chronic liver diseases. Recent evidence suggests that effects of dietary foods on health care and human diseases are related to both the immune reaction and the microbiome. The gut-microbiome and intestinal immune system play a central role in the control of bacterial translocation-induced liver disease. Dysbiosis, small intestinal bacterial overgrowth, translocation, endotoxemia, and the direct effects of metabolites are the main events in the gut-liver axis, and immune responses act on every pathways of chronic liver disease. Microbiome-derived metabolites or bacteria themselves regulate immune cell functions such as recognition or activation of receptors, the control of gene expression by epigenetic change, activation of immune cells, and the integration of cellular metabolism. Here, we reviewed recent reports about the immunologic role of gut microbiotas in liver disease, highlighting the role of diet in chronic liver disease.
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21
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Dufour JF, Scherer R, Balp MM, McKenna SJ, Janssens N, Lopez P, Pedrosa M. The global epidemiology of nonalcoholic steatohepatitis (NASH) and associated risk factors–A targeted literature review. ENDOCRINE AND METABOLIC SCIENCE 2021. [DOI: 10.1016/j.endmts.2021.100089] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
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22
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Al-Muzafar HM, Alshehri FS, Amin KA. The role of pioglitazone in antioxidant, anti-inflammatory, and insulin sensitivity in a high fat-carbohydrate diet-induced rat model of insulin resistance. ACTA ACUST UNITED AC 2021; 54:e10782. [PMID: 34037093 PMCID: PMC8148887 DOI: 10.1590/1414-431x2020e10782] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 03/15/2021] [Indexed: 01/13/2023]
Abstract
We explored the cascade effects of a high fat-carbohydrate diet (HFCD) and pioglitazone (an anti-diabetic therapy used to treat type 2 diabetes mellitus (T2DM)) on lipid profiles, oxidative stress/antioxidant, insulin, and inflammatory biomarkers in a rat model of insulin resistance. Sixty albino rats (80-90 g) were randomly divided into three dietary groups; 1) standard diet; 2) HFCD diet for 12 weeks to induce an in vivo model of insulin resistance; and 3) HFCD diet plus pioglitazone. Blood and tissue samples were taken to assess hepatic function, lipid profiles, oxidative biomarkers, malondialdehyde (MDA) levels, antioxidant defense biomarkers, including reduced glutathione (GSH), superoxide dismutase (SOD), and the inflammatory markers interleukin-6 (IL-6) and tumor necrotic factor (TNF-α). HFCD-fed rats had significantly (P≤0.05) increased serum triacylglycerol (TG), total cholesterol (TC), low-density lipoprotein (LDL), alanine transaminase (ALT), and bilirubin levels, but decreased high-density lipoprotein (HDL) levels compared with the normal group. Moreover, serum leptin, resistin, TNF-α, and IL-6 levels were increased significantly in HFCD animals compared with controls. Similarly, HFCD-induced insulin resistance caused antioxidant and cytokine disturbances, which are important therapy targets for pioglitazone. Importantly, administration of this drug ameliorated these changes, normalized leptin and resistin and inflammatory markers by reducing TNF-α levels. Metabolic cascades of elevated lipid profiles, oxidative stress, insulin, and inflammatory biomarkers are implicated in insulin resistance progression. HFCD induced metabolic cascades comprising hypertriglyceridemia, hyperglycemia, insulin resistance, obesity-associated hormones, and inflammatory biomarkers may be alleviated using pioglitazone.
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Affiliation(s)
- H M Al-Muzafar
- Department of Chemistry, College of Science, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia.,Basic & Applied Scientific Research Center, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - F S Alshehri
- Department of Chemistry, College of Science, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia.,Basic & Applied Scientific Research Center, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - K A Amin
- Department of Chemistry, College of Science, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia.,Basic & Applied Scientific Research Center, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
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23
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Real-World Burden of Nonalcoholic Steatohepatitis. Clin Gastroenterol Hepatol 2021; 19:1020-1029.e7. [PMID: 32634622 DOI: 10.1016/j.cgh.2020.06.064] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Revised: 06/22/2020] [Accepted: 06/26/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Nonalcoholic steatohepatitis (NASH) is associated with an increase in healthcare resource use and poor health-related quality of life (HRQoL). We assessed the humanistic and economic burden of NASH, disease management, and patient journey. METHODS We performed a cross-sectional analysis of data, collected from July through November 2017, from the Growth from Knowledge Disease Atlas Real-World Evidence program, reported by physicians in United States, France, and Germany. We extracted demographic and medical data from medical records. Some patients voluntarily completed a survey that provided information on disease history, treatment satisfaction, and patient-reported outcomes. RESULTS We analyzed data from 1216 patients (mean age, 54.9±12.3 years; 57.5% male; mean body mass index, 31.7±6.9); 64.6% had biopsy-confirmed NASH and comorbidities were recorded for 41.3%. Treatments included lifestyle modification (64.6%) or use of statins (25.0%), vitamin E (23.5%), or metformin (20.2%). Patients with biopsy-confirmed NASH reported more physician (4.5 vs 3.7) and outpatient visits (1.8 vs1.4) than patients with suspected NASH not confirmed by biopsy. Among the 299 patients who completed the survey, 47.8% reported various symptoms associated to their NASH. Symptomatic patients reported significantly lower HRQoL than patients without symptoms. CONCLUSIONS In an analysis of data from 3 countries, we found NASH to be associated with regular use of medical resources; patients with symptoms of NASH had reduced HRQoL. The burden of NASH appears to be underestimated. Studies are needed to determine the burden of NASH by fibrosis stage and disease severity.
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24
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Zhao QY, Ge LH, Zhang K, Chen HF, Zhan XX, Yang Y, Dang QL, Zheng Y, Zhou HB, Lyu JX, Fang HZ. Assessment of mitochondrial function in metabolic dysfunction-associated fatty liver disease using obese mouse models. Zool Res 2020; 41:539-551. [PMID: 32786176 PMCID: PMC7475011 DOI: 10.24272/j.issn.2095-8137.2020.051] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) is characterized by deregulated hepatic lipid metabolism; however, the association between MAFLD development and mitochondrial dysfunction has yet to be confirmed. Herein, we employed high-resolution respirometry, blue native polyacrylamide gel electrophoresis-based in-gel activity measurement and immunoblot analysis to assess mitochondrial function in obesity-induced mouse models with varying degrees of MAFLD. Results showed a slight but significant decrease in hepatic mitochondrial respiration in some MAFLD mice compared to mice fed a standard diet. However, the activities and levels of mitochondrial oxidative phosphorylation complexes remained unchanged during obesity-induced MAFLD progression. These results suggest that mitochondrial function, particularly oxidative phosphorylation, was mildly affected during obesity-induced MAFLD development. Moreover, transcriptome profiling of mouse and human liver tissues with varying degrees of MAFLD revealed that the decreased activation of mitochondria-related pathways was only associated with MAFLD of a high histological grade, whereas the major regulators of mitochondrial biogenesis were not altered in mice or humans during MAFLD development. Collectively, our results suggest that impaired hepatic mitochondrial function is not closely associated with obesity-induced MAFLD. Therefore, therapeutic strategies targeting mitochondria for the treatment of MAFLD should be reconsidered.
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Affiliation(s)
- Qiong-Ya Zhao
- School of Laboratory Medicine, Hangzhou Medical College, Hangzhou, Zhejiang 310053, China.,Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Ling-Hong Ge
- Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310005, China
| | - Kun Zhang
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Hai-Feng Chen
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Xin-Xin Zhan
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Yue Yang
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Qing-Lin Dang
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Yi Zheng
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Huai-Bin Zhou
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Jian-Xin Lyu
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. E-mail:
| | - He-Zhi Fang
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. E-mail:
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25
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Chella Krishnan K, Floyd RR, Sabir S, Jayasekera DW, Leon-Mimila PV, Jones AE, Cortez AA, Shravah V, Péterfy M, Stiles L, Canizales-Quinteros S, Divakaruni AS, Huertas-Vazquez A, Lusis AJ. Liver Pyruvate Kinase Promotes NAFLD/NASH in Both Mice and Humans in a Sex-Specific Manner. Cell Mol Gastroenterol Hepatol 2020; 11:389-406. [PMID: 32942044 PMCID: PMC7788245 DOI: 10.1016/j.jcmgh.2020.09.004] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 08/31/2020] [Accepted: 09/03/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS The etiology of nonalcoholic fatty liver disease (NAFLD) is poorly understood, with males and certain populations exhibiting markedly increased susceptibility. Using a systems genetics approach involving multi-omic analysis of ∼100 diverse inbred strains of mice, we recently identified several candidate genes driving NAFLD. We investigated the role of one of these, liver pyruvate kinase (L-PK or Pklr), in NAFLD by using patient samples and mouse models. METHODS We examined L-PK expression in mice of both sexes and in a cohort of bariatric surgery patients. We used liver-specific loss- and gain-of-function strategies in independent animal models of diet-induced steatosis and fibrosis. After treatment, we measured several metabolic phenotypes including obesity, insulin resistance, dyslipidemia, liver steatosis, and fibrosis. Liver tissues were used for gene expression and immunoblotting, and liver mitochondria bioenergetics was characterized. RESULTS In both mice and humans, L-PK expression is up-regulated in males via testosterone and is strongly associated with NAFLD severity. In a steatosis model, L-PK silencing in male mice improved glucose tolerance, insulin sensitivity, and lactate/pyruvate tolerance compared with controls. Furthermore, these animals had reduced plasma cholesterol levels and intrahepatic triglyceride accumulation. Conversely, L-PK overexpression in male mice resulted in augmented disease phenotypes. In contrast, female mice overexpressing L-PK were unaffected. Mechanistically, L-PK altered mitochondrial pyruvate flux and its incorporation into citrate, and this, in turn, increased liver triglycerides via up-regulated de novo lipogenesis and increased PNPLA3 levels accompanied by mitochondrial dysfunction. Also, L-PK increased plasma cholesterol levels via increased PCSK9 levels. On the other hand, L-PK silencing reduced de novo lipogenesis and PNPLA3 and PCSK9 levels and improved mitochondrial function. Finally, in fibrosis model, we demonstrate that L-PK silencing in male mice reduced both liver steatosis and fibrosis, accompanied by reduced de novo lipogenesis and improved mitochondrial function. CONCLUSIONS L-PK acts in a male-specific manner in the development of liver steatosis and fibrosis. Because NAFLD/nonalcoholic steatohepatitis exhibit sexual dimorphism, our results have important implications for the development of personalized therapeutics.
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Affiliation(s)
- Karthickeyan Chella Krishnan
- Department of Medicine/Division of Cardiology, University of California, Los Angeles, California,Correspondence Address correspondence to: Karthickeyan Chella Krishnan, PhD, UCLA Department of Medicine/Division of Cardiology, 650 Charles E. Young Drive South, Box 951679, Los Angeles, California 90095-1679. fax: (310) 794-7345, or
| | - Raquel R. Floyd
- Department of Biology, University of California, Los Angeles, California
| | - Simon Sabir
- Department of Psychology, University of California, Los Angeles, California
| | - Dulshan W. Jayasekera
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, California
| | - Paola V. Leon-Mimila
- Department of Medicine/Division of Cardiology, University of California, Los Angeles, California,Facultad de Química, UNAM/Instituto Nacional de Medicina Genómica (INMEGEN), Unidad de Genómica de Poblaciones Aplicada a la Salud, Mexico City, Mexico
| | - Anthony E. Jones
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, California
| | - Angel A. Cortez
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, California
| | - Varun Shravah
- Department of Chemistry, University of California, Los Angeles, California
| | - Miklós Péterfy
- Department of Medicine/Division of Cardiology, University of California, Los Angeles, California,Department of Basic Medical Sciences, Western University of Health Sciences, Pomona, California
| | - Linsey Stiles
- Department of Medicine/Division of Endocrinology, University of California, Los Angeles, California
| | - Samuel Canizales-Quinteros
- Facultad de Química, UNAM/Instituto Nacional de Medicina Genómica (INMEGEN), Unidad de Genómica de Poblaciones Aplicada a la Salud, Mexico City, Mexico
| | - Ajit S. Divakaruni
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, California
| | - Adriana Huertas-Vazquez
- Department of Medicine/Division of Cardiology, University of California, Los Angeles, California
| | - Aldons J. Lusis
- Department of Medicine/Division of Cardiology, University of California, Los Angeles, California,Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, California,Department of Human Genetics, University of California, Los Angeles, California,Aldons J. Lusis, PhD, UCLA Department of Medicine/Division of Cardiology, 650 Charles E. Young Drive South, Box 951679, Los Angeles, California 90095-1679.
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26
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Oni ET, Figueredo V, Aneni E, Veladar E, McEvoy JW, Blaha MJ, Blumenthal RS, Conceicao RD, Carvalho JAM, Santos RD, Nasir K. Non-Alcoholic Fatty Liver Disease Modifies Serum Gamma-Glutamyl Transferase in Cigarette Smokers. J Clin Med Res 2020; 12:472-482. [PMID: 32849935 PMCID: PMC7430878 DOI: 10.14740/jocmr3932] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Accepted: 01/22/2020] [Indexed: 11/11/2022] Open
Abstract
Background Serum gamma-glutamyl transferase (GGT) is a marker of oxidative stress, associated with increased cardiovascular (CV) risk. The impact of smoking on oxidative stress may be aggravated in individuals with non-alcoholic fatty liver disease (NAFLD). We aimed to ascertain the association of smoking on GGT levels in the presence or absence of NAFLD. Methods We evaluated 6,354 healthy subjects (43 ± 10 years, 79% males) without clinical cardiovascular disease (CVD) undergoing an employer-sponsored physical between December 2008 and December 2010. NAFLD was diagnosed by ultrasound and participants were categorized as current or non-smokers by self report. A multivariate linear regression of the cross-sectional association between smoking and GGT was conducted based on NAFLD status. Results The prevalence of NAFLD was 36% (n = 2,299) and 564 (9%) were current smokers. Smokers had significantly higher GGT levels in the presence of NAFLD (P < 0.001). After multivariable adjustment, current smoking was associated with 4.65 IU/L higher GGT level, P < 0.001, compared to non-smokers. When stratified by NAFLD, the magnitude of this association was higher in subjects with NAFLD (β-coefficient: 11.12; 95% confidence interval (CI): 5.76 - 16.48; P < 0.001); however, no such relationship was observed in those without NAFLD (β: -0.02; 95% CI: -3.59, 3.56; P = 0.992). Overall the interaction of NAFLD and smoking with GGT levels as markers of oxidative stress was statistically significant. Conclusions Smoking is independently associated with significantly increased oxidative stress as measured by GGT level. This association demonstrates effect modification by NAFLD status, suggesting that smoking may intensify CV risk in individuals with NAFLD.
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Affiliation(s)
- Ebenezer T Oni
- Cardiology Division, Heart and Vascular Institute, Einstein Medical Center, Philadelphia, PA, USA
| | - Vincent Figueredo
- St. Mary Medical Center, 1203 Langhorne-Newtown Road, Suite 320, Langhorne, PA 19047, USA
| | - Ehimen Aneni
- Section of Cardiovascular Medicine, Department of Medicine, Yale University School of Medicine
| | - Emir Veladar
- Center of Advanced Analytics, Baptist Health South Florida, 8900 North Kendall Drive, Miami, FL 33176, USA
| | - John W McEvoy
- The Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Baltimore, MD, USA
| | - Michael J Blaha
- The Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Baltimore, MD, USA.,Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Roger S Blumenthal
- The Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Baltimore, MD, USA
| | - Raquel D Conceicao
- Preventive Medicine Center Hospital Israelita Albert Einstein, Sao Paulo, Brazil
| | - Jose A M Carvalho
- Preventive Medicine Center Hospital Israelita Albert Einstein, Sao Paulo, Brazil
| | - Raul D Santos
- Preventive Medicine Center Hospital Israelita Albert Einstein, Sao Paulo, Brazil.,Lipid Clinic-Heart Institute (InCor) University of Sao Paulo Medical School Hospital, Sao Paulo, Brazil
| | - Khurram Nasir
- Houston Methodist, Debakey Heart and Vascualr Institute, Houston, TX, USA
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Zhao P, Saltiel AR. From overnutrition to liver injury: AMP-activated protein kinase in nonalcoholic fatty liver diseases. J Biol Chem 2020; 295:12279-12289. [PMID: 32651233 PMCID: PMC7443502 DOI: 10.1074/jbc.rev120.011356] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 06/24/2020] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver diseases (NAFLDs), especially nonalcoholic steatohepatitis (NASH), have become a major cause of liver transplant and liver-associated death. However, the pathogenesis of NASH is still unclear. Currently, there is no FDA-approved medication to treat this devastating disease. AMP-activated protein kinase (AMPK) senses energy status and regulates metabolic processes to maintain homeostasis. The activity of AMPK is regulated by the availability of nutrients, such as carbohydrates, lipids, and amino acids. AMPK activity is increased by nutrient deprivation and inhibited by overnutrition, inflammation, and hypersecretion of certain anabolic hormones, such as insulin, during obesity. The repression of hepatic AMPK activity permits the transition from simple steatosis to hepatocellular death; thus, activation might ameliorate multiple aspects of NASH. Here we review the pathogenesis of NAFLD and the impact of AMPK activity state on hepatic steatosis, inflammation, liver injury, and fibrosis during the transition of NAFL to NASH and liver failure.
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Affiliation(s)
- Peng Zhao
- Department of Medicine, University of California San Diego, La Jolla, California, USA
| | - Alan R Saltiel
- Department of Medicine, University of California San Diego, La Jolla, California, USA; Department of Pharmacology, University of California San Diego, La Jolla, California, USA.
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Xin X, Chen C, Hu YY, Feng Q. Protective effect of genistein on nonalcoholic fatty liver disease (NAFLD). Biomed Pharmacother 2019; 117:109047. [PMID: 31176163 DOI: 10.1016/j.biopha.2019.109047] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2019] [Revised: 05/26/2019] [Accepted: 05/29/2019] [Indexed: 02/07/2023] Open
Abstract
NAFLD is a vital health problem worldwide; however, no effective treatment is currently available for NAFLD. Intensive studies have indicated the efficacy of genistein (GE), a bioactive isoflavone extracted from soy, in treating NAFLD. In addition to its oestrogen-like effects, GE is known to have multiple molecular effects, for instance, lipid and glucose metabolism-promoting effects and activities against lipid peroxidation, inflammation, fibrosis, and NAFLD-related tumours. Here, this review summarizes the potential role of GE in the treatment and prevention of NAFLD and some of the currently known targets and signalling pathways of GE in NAFLD.
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Affiliation(s)
- Xin Xin
- Institute of Liver diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Cheng Chen
- Institute of Liver diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Yi-Yang Hu
- Institute of Liver diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, 201203, China; Key Laboratory of Liver and Kidney Diseases, Shanghai University of Traditional Chinese Medicine, Ministry of Education, Shanghai, 201203, China
| | - Qin Feng
- Institute of Liver diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, 201203, China; Key Laboratory of Liver and Kidney Diseases, Shanghai University of Traditional Chinese Medicine, Ministry of Education, Shanghai, 201203, China.
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Theodotou M, Fokianos K, Moniatis D, Kadlenic R, Chrysikou A, Aristotelous A, Mouzouridou A, Diakides J, Stavrou E. Effect of resveratrol on non-alcoholic fatty liver disease. Exp Ther Med 2019; 18:559-565. [PMID: 31316594 PMCID: PMC6566048 DOI: 10.3892/etm.2019.7607] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Accepted: 10/26/2018] [Indexed: 12/15/2022] Open
Abstract
The aim of the present study was to investigate the effect of a micronized formulation of trans-resveratrol in humans with non-alcoholic fatty liver disease (NAFLD). Trans-Resveratrol has been used in the form of micronized formulation, which is better absorbed, has strong antioxidants effects, is more effective than plain resveratrol formulations and is circulated on the market as a food supplement. Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a stilbenoid and a phytoalexin produced by several plants. NAFLD is an increasing clinical problem involving the liver for which effective treatments are required. The present study was based on two patient groups. The study, which commenced on April 2013 and finished on April 2015, included 44 patients, aged 29–70 years, with an average weight of 84.6 kg (n=22 per group; 28 men and 16 women) who were randomly assigned to groups and given 50 mg Evelor capsule (n=22) and 200 mg Evelor H tablet (n=22) correspondingly on a daily basis. The patients were followed up for 6 months. Quantity fat measurements, with ultrasound on the liver and kidney, were carried out. There was an initial measurement (time 1) and one after six months (time 2). The study results showed the effects of Trans-resveratrol micronized formulation in reducing the liver fat, as well as decreasing hepatic enzymes, serum glutamate pyruvic transaminase (SGPT) and gamma-glutamyl transpeptidase (g-GT) and insulin resistance. At the end of the study, the statistical analysis showed a statistically significant reduction on the liver fat. These data demonstrate that use of Trans-resveratrol micronized formulation improves features of NAFLD, and prevents liver damage. Thus, Trans-resveratrol micronized formulation can be a new treatment method for NAFLD.
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Affiliation(s)
- Marios Theodotou
- Private Practice, Limassol 3020, Cyprus.,Riegler Ltd., Institute of Medical Clinical Trials, Limassol 3020, Cyprus
| | - Konstantinos Fokianos
- Department of Mathematics and Statistics, University of Cyprus, Nicosia 20537, Cyprus
| | - Demetris Moniatis
- Riegler Ltd., Institute of Medical Clinical Trials, Limassol 3020, Cyprus
| | - Rudolf Kadlenic
- Riegler Ltd., Institute of Medical Clinical Trials, Limassol 3020, Cyprus
| | - Asimina Chrysikou
- Riegler Ltd., Institute of Medical Clinical Trials, Limassol 3020, Cyprus
| | | | | | - John Diakides
- Riegler Ltd., Institute of Medical Clinical Trials, Limassol 3020, Cyprus
| | - Eliza Stavrou
- Riegler Ltd., Institute of Medical Clinical Trials, Limassol 3020, Cyprus
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Yang Z, Zhu M, Zhang Y, Wen B, An H, Ou X, Xiong Y, Lin H, Liu Z, Huang J. Coadministration of epigallocatechin‐3‐gallate (EGCG) and caffeine in low dose ameliorates obesity and nonalcoholic fatty liver disease in obese rats. Phytother Res 2019; 33:1019-1026. [DOI: 10.1002/ptr.6295] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Revised: 11/16/2018] [Accepted: 01/02/2019] [Indexed: 01/01/2023]
Affiliation(s)
- Zhe Yang
- National Research Center of Engineering Technology for Utilization of Functional Ingredients from BotanicalsHunan Agricultural University Changsha China
- Collaborative Innovation Centre of Utilization of Functional Ingredients from Botanicals, Hunan Agricultural University Changsha China
- Key Laboratory of Tea Science of Ministry of Education, Hunan Agricultural University Changsha China
| | - Ming‐zhi Zhu
- National Research Center of Engineering Technology for Utilization of Functional Ingredients from BotanicalsHunan Agricultural University Changsha China
| | - Yang‐bo Zhang
- Collaborative Innovation Centre of Utilization of Functional Ingredients from Botanicals, Hunan Agricultural University Changsha China
| | - Bei‐bei Wen
- National Research Center of Engineering Technology for Utilization of Functional Ingredients from BotanicalsHunan Agricultural University Changsha China
| | - Hui‐min An
- Collaborative Innovation Centre of Utilization of Functional Ingredients from Botanicals, Hunan Agricultural University Changsha China
| | - Xing‐chang Ou
- National Research Center of Engineering Technology for Utilization of Functional Ingredients from BotanicalsHunan Agricultural University Changsha China
| | - Yi‐fan Xiong
- Collaborative Innovation Centre of Utilization of Functional Ingredients from Botanicals, Hunan Agricultural University Changsha China
- Key Laboratory of Tea Science of Ministry of Education, Hunan Agricultural University Changsha China
| | - Hai‐yan Lin
- Collaborative Innovation Centre of Utilization of Functional Ingredients from Botanicals, Hunan Agricultural University Changsha China
| | - Zhong‐hua Liu
- National Research Center of Engineering Technology for Utilization of Functional Ingredients from BotanicalsHunan Agricultural University Changsha China
- Collaborative Innovation Centre of Utilization of Functional Ingredients from Botanicals, Hunan Agricultural University Changsha China
- Key Laboratory of Tea Science of Ministry of Education, Hunan Agricultural University Changsha China
| | - Jian‐an Huang
- Key Laboratory of Tea Science of Ministry of Education, Hunan Agricultural University Changsha China
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Gou XJ, Gao S, Chen L, Feng Q, Hu YY. A Metabolomic Study on the Intervention of Traditional Chinese Medicine Qushi Huayu Decoction on Rat Model of Fatty Liver Induced by High-Fat Diet. BIOMED RESEARCH INTERNATIONAL 2019; 2019:5920485. [PMID: 30881991 PMCID: PMC6383432 DOI: 10.1155/2019/5920485] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Accepted: 01/10/2019] [Indexed: 12/23/2022]
Abstract
Qushi Huayu Decoction (QHD), an important clinically proved herbal formula, has been reported to be effective in treating fatty liver induced by high-fat diet in rats. However, the mechanism of action has not been clarified at the metabolic level. In this study, a urinary metabolomic method based on gas chromatography-mass spectrometry (GC-MS) coupled with pattern recognition analysis was performed in three groups (control, model, and QHD group), to explore the effect of QHD on fatty liver and its mechanism of action. There was obvious separation between the model group and control group, and the QHD group showed a tendency of recovering to the control group in metabolic profiles. Twelve candidate biomarkers were identified and used to explore the possible mechanism. Then, a pathway analysis was performed using MetaboAnalyst 3.0 to illustrate the pathways of therapeutic action of QHD. QHD reversed the urinary metabolite abnormalities (tryptophan, uridine, and phenylalanine, etc.). Fatty liver might be prevented by QHD through regulating the dysfunctions of phenylalanine, tyrosine, and tryptophan biosynthesis, phenylalanine metabolism, and tryptophan metabolism. This work demonstrated that metabolomics might be helpful for understanding the mechanism of action of traditional Chinese medicine for future clinical evaluation.
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Affiliation(s)
- Xiao-jun Gou
- Central Laboratory, Baoshan District Hospital of Integrated Traditional Chinese and Western Medicine of Shanghai, Shanghai University of Traditional Chinese Medicine, Shanghai 201999, China
| | - Shanshan Gao
- School of Pharmacy, Shaanxi University of Traditional Chinese Medicine, Yangxian, Shaanxi 712046, China
| | - Liang Chen
- Nantong Hospital Affiliated to Nanjing University of Chinese Medicine, Nantong, Jiangsu 226001, China
| | - Qin Feng
- Institute of Liver Disease, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yi-yang Hu
- Institute of Liver Disease, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
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Cook NS, Nagar SH, Jain A, Balp MM, Mayländer M, Weiss O, Chatterjee S. Understanding Patient Preferences and Unmet Needs in Non-alcoholic Steatohepatitis (NASH): Insights from a Qualitative Online Bulletin Board Study. Adv Ther 2019; 36:478-491. [PMID: 30547371 PMCID: PMC6824346 DOI: 10.1007/s12325-018-0856-0] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Indexed: 02/07/2023]
Abstract
INTRODUCTION The aim of this work was to understand how patients with non-alcoholic steatohepatitis (NASH) perceive their disease, unmet needs, and expectations regarding future treatment through online bulletin board (OBB) qualitative research. METHODS OBB is an asynchronous online qualitative market research tool that provides an open forum for interactive discussion among participants. Patients with NASH were recruited via physician referral and completed a screener questionnaire to ensure their eligibility and willingness to participate. A trained moderator managed the discussion that allowed open answers and responses to other participants' posts. Patient responses were analyzed using a combination of different qualitative analytical tools. RESULTS The OBB ran for 4 days and included 16 patients (n = 8, UK; n = 8, US) with NASH (fibrosis stages F1-F3) and comorbidities including diabetes/prediabetes (n = 9) and obesity (n = 12). The key insights were (1) patients with NASH have a poor understanding of the disease, its progression, and management-they feel a lack of adequate educational support from their physicians; (2) diagnosis of NASH is incidental in most cases, mainly because patients fail to spontaneously associate their signs or symptoms with their liver condition; (3) comorbidities (obesity and diabetes) are more concerning to patients than NASH; and (4) patients perceive that NASH impacts their social life and work performance in more advanced stages. CONCLUSIONS This OBB provided valuable patient insights into NASH disease perception and management and revealed unmet need areas. In light of no approved therapies, these patient insights can inform early drug development strategies and stakeholder discussions on NASH. FUNDING Novartis Pharma AG, Basel.
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Bae J, Kumazoe M, Fujimura Y, Tachibana H. Diallyl disulfide potentiates anti-obesity effect of green tea in high-fat/high-sucrose diet-induced obesity. J Nutr Biochem 2019; 64:152-161. [DOI: 10.1016/j.jnutbio.2018.10.014] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2018] [Revised: 10/10/2018] [Accepted: 10/29/2018] [Indexed: 12/22/2022]
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Goodarzi R, Sabzian K, Shishehbor F, Mansoori A. Does turmeric/curcumin supplementation improve serum alanine aminotransferase and aspartate aminotransferase levels in patients with nonalcoholic fatty liver disease? A systematic review and meta-analysis of randomized controlled trials. Phytother Res 2019; 33:561-570. [DOI: 10.1002/ptr.6270] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 11/30/2018] [Accepted: 12/09/2018] [Indexed: 01/20/2023]
Affiliation(s)
- Reza Goodarzi
- Nutrition and Metabolic Diseases Research Center; Ahvaz Jundishapur University of Medical Sciences; Ahvaz Iran
| | - Kamran Sabzian
- Pediatric Medicine Department, Faculty of Medicine; Lorestan University of Medical Sciences; Lorestan Iran
| | - Farideh Shishehbor
- Nutrition and Metabolic Diseases Research Center; Ahvaz Jundishapur University of Medical Sciences; Ahvaz Iran
| | - Anahita Mansoori
- Nutrition and Metabolic Diseases Research Center; Ahvaz Jundishapur University of Medical Sciences; Ahvaz Iran
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Hui ST, Kurt Z, Tuominen I, Norheim F, C.Davis R, Pan C, Dirks DL, Magyar CE, French SW, Chella Krishnan K, Sabir S, Campos‐Pérez F, Méndez‐Sánchez N, Macías‐Kauffer L, León‐Mimila P, Canizales‐Quinteros S, Yang X, Beaven SW, Huertas‐Vazquez A, Lusis AJ. The Genetic Architecture of Diet-Induced Hepatic Fibrosis in Mice. Hepatology 2018; 68:2182-2196. [PMID: 29907965 PMCID: PMC6269199 DOI: 10.1002/hep.30113] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Accepted: 05/12/2018] [Indexed: 12/21/2022]
Abstract
We report the genetic analysis of a "humanized" hyperlipidemic mouse model for progressive nonalcoholic steatohepatitis (NASH) and fibrosis. Mice carrying transgenes for human apolipoprotein E*3-Leiden and cholesteryl ester transfer protein and fed a "Western" diet were studied on the genetic backgrounds of over 100 inbred mouse strains. The mice developed hepatic inflammation and fibrosis that was highly dependent on genetic background, with vast differences in the degree of fibrosis. Histological analysis showed features characteristic of human NASH, including macrovesicular steatosis, hepatocellular ballooning, inflammatory foci, and pericellular collagen deposition. Time course experiments indicated that while hepatic triglyceride levels increased steadily on the diet, hepatic fibrosis occurred at about 12 weeks. We found that the genetic variation predisposing to NASH and fibrosis differs markedly from that predisposing to simple steatosis, consistent with a multistep model in which distinct genetic factors are involved. Moreover, genome-wide association identified distinct genetic loci contributing to steatosis and NASH. Finally, we used hepatic expression data from the mouse panel and from 68 bariatric surgery patients with normal liver, steatosis, or NASH to identify enriched biological pathways. Conclusion: The pathways showed substantial overlap between our mouse model and the human disease.
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Affiliation(s)
- Simon T. Hui
- Department of Medicine, Division of CardiologyDavid Geffen School of MedicineLos AngelesCA
| | - Zeyneb Kurt
- Department of Integrative Biology and PhysiologyUniversity of CaliforniaLos AngelesCA
| | - Iina Tuominen
- Department of Medicine, Division of Digestive Diseases & Pfleger Liver Institute and Center for Obesity and Metabolic Health (COMET)David Geffen School of MedicineLos AngelesCA
| | - Frode Norheim
- Department of Medicine, Division of CardiologyDavid Geffen School of MedicineLos AngelesCA
| | - Richard C.Davis
- Department of Medicine, Division of CardiologyDavid Geffen School of MedicineLos AngelesCA
| | - Calvin Pan
- Department of Medicine, Division of CardiologyDavid Geffen School of MedicineLos AngelesCA
| | - Darwin L. Dirks
- Department of Medicine, Division of CardiologyDavid Geffen School of MedicineLos AngelesCA
| | - Clara E. Magyar
- Department of Pathology & Laboratory Medicine, David Geffen School of MedicineUniversity of CaliforniaLos AngelesCA
| | - Samuel W. French
- Department of Pathology & Laboratory Medicine, David Geffen School of MedicineUniversity of CaliforniaLos AngelesCA
| | | | - Simon Sabir
- Department of Medicine, Division of CardiologyDavid Geffen School of MedicineLos AngelesCA
| | - Francisco Campos‐Pérez
- Clínica Integral de Cirugía para la Obesidad y Enfermedades MetabólicasHospital General Dr. Rubén LéneroMexico CityMexico
| | | | - Luis Macías‐Kauffer
- Facultad de Química, UNAM/Instituto Nacional de Medicina Genómica (INMEGEN)Unidad de Genómica de Poblaciones Aplicada a la SaludMexico CityMexico
| | - Paola León‐Mimila
- Facultad de Química, UNAM/Instituto Nacional de Medicina Genómica (INMEGEN)Unidad de Genómica de Poblaciones Aplicada a la SaludMexico CityMexico
| | - Samuel Canizales‐Quinteros
- Facultad de Química, UNAM/Instituto Nacional de Medicina Genómica (INMEGEN)Unidad de Genómica de Poblaciones Aplicada a la SaludMexico CityMexico
| | - Xia Yang
- Department of Integrative Biology and PhysiologyUniversity of CaliforniaLos AngelesCA
| | - Simon W. Beaven
- Department of Medicine, Division of Digestive Diseases & Pfleger Liver Institute and Center for Obesity and Metabolic Health (COMET)David Geffen School of MedicineLos AngelesCA
| | | | - Aldons J. Lusis
- Department of Medicine, Division of CardiologyDavid Geffen School of MedicineLos AngelesCA
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Kurt Z, Barrere-Cain R, LaGuardia J, Mehrabian M, Pan C, Hui ST, Norheim F, Zhou Z, Hasin Y, Lusis AJ, Yang X. Tissue-specific pathways and networks underlying sexual dimorphism in non-alcoholic fatty liver disease. Biol Sex Differ 2018; 9:46. [PMID: 30343673 PMCID: PMC6196429 DOI: 10.1186/s13293-018-0205-7] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 10/03/2018] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) encompasses benign steatosis and more severe conditions such as non-alcoholic steatohepatitis (NASH), cirrhosis, and liver cancer. This chronic liver disease has a poorly understood etiology and demonstrates sexual dimorphisms. We aim to examine the molecular mechanisms underlying sexual dimorphisms in NAFLD pathogenesis through a comprehensive multi-omics study. We integrated genomics (DNA variations), transcriptomics of liver and adipose tissue, and phenotypic data of NAFLD derived from female mice of ~ 100 strains included in the hybrid mouse diversity panel (HMDP) and compared the NAFLD molecular pathways and gene networks between sexes. RESULTS We identified both shared and sex-specific biological processes for NAFLD. Adaptive immunity, branched chain amino acid metabolism, oxidative phosphorylation, and cell cycle/apoptosis were shared between sexes. Among the sex-specific pathways were vitamins and cofactors metabolism and ion channel transport for females, and phospholipid, lysophospholipid, and phosphatidylinositol metabolism and insulin signaling for males. Additionally, numerous lipid and insulin-related pathways and inflammatory processes in the adipose and liver tissue appeared to show more prominent association with NAFLD in male HMDP. Using data-driven network modeling, we identified plausible sex-specific and tissue-specific regulatory genes as well as those that are shared between sexes. These key regulators orchestrate the NAFLD pathways in a sex- and tissue-specific manner. Gonadectomy experiments support that sex hormones may partially underlie the sexually dimorphic genes and pathways involved in NAFLD. CONCLUSIONS Our multi-omics integrative study reveals sex- and tissue-specific genes, processes, and networks underlying sexual dimorphism in NAFLD and may facilitate sex-specific precision medicine.
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Affiliation(s)
- Zeyneb Kurt
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA USA
| | - Rio Barrere-Cain
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA USA
| | - Jonnby LaGuardia
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA USA
| | - Margarete Mehrabian
- Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA USA
| | - Calvin Pan
- Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA USA
| | - Simon T Hui
- Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA USA
| | - Frode Norheim
- Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA USA
| | - Zhiqiang Zhou
- Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA USA
| | - Yehudit Hasin
- Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA USA
| | - Aldons J Lusis
- Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA USA
| | - Xia Yang
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA USA
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Abstract
PURPOSE OF REVIEW Sex differences are pervasive in metabolic and cardiovascular traits, yet they have often been ignored in human and animal model research. Sex differences can arise from reversible hormonal effects, from irreversible organizational (developmental) processes, and from gene expression differences from the X and Y chromosomes. We briefly review our current understanding of the impact of these factors in metabolic traits and disorders, with an emphasis on the recent literature. RECENT FINDINGS Novel sex differences continue to be identified for metabolic and cardiovascular traits. For example, it is now clear that gut microbiota tend to differ between men and women, with potentially large implications for disease susceptibility. Also, tissue-specific gene regulation differs between men and women, contributing to differential metabolism. These new insights will open up personalized therapeutic avenues for cardiometabolic diseases. SUMMARY Sex differences in body fat distribution, glucose homeostasis, insulin signaling, ectopic fat accumulation, and lipid metabolism during normal growth and in response to hormonal or nutritional imbalance are mediated partly through sex hormones and the sex chromosome complement. Most of these differences are mediated in a tissue-specific manner. Important future goals are to better understand the interactions between genetic variation and sex differences, and to bring an understanding of sex differences into clinical practice.
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Affiliation(s)
| | | | - Aldons J. Lusis
- Department of Medicine/Division of Cardiology
- Department of Micro-biology, Immunology and Molecular Genetics
- Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California, USA
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Baker PR, Friedman JE. Mitochondrial role in the neonatal predisposition to developing nonalcoholic fatty liver disease. J Clin Invest 2018; 128:3692-3703. [PMID: 30168806 DOI: 10.1172/jci120846] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a global epidemic in obese children and adults, and the onset might have fetal origins. A growing body of evidence supports the role of developmental programming, whereby the maternal environment affects fetal and infant development, altering the risk profile for disease later in life. Human and nonhuman primate studies of maternal obesity demonstrate that risk factors for pediatric obesity and NAFLD begin in utero. The pathologic mechanisms for NAFLD are multifactorial but have centered on altered mitochondrial function/dysfunction that might precede insulin resistance. Compared with the adult liver, the fetal liver has fewer mitochondria, low activity of the fatty acid metabolic enzyme carnitine palmitoyl-CoA transferase-1, and little or no gluconeogenesis. Exposure to excess maternal fuels during fetal life uniquely alters hepatic fatty acid oxidation, tricarboxylic acid cycle activity, de novo lipogenesis, and mitochondrial health. These events promote increased oxidative stress and excess triglyceride storage, and, together with altered immune function and epigenetic changes, they prime the fetal liver for NAFLD and might drive the risk for nonalcoholic steatohepatitis in the next generation.
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Affiliation(s)
- Peter R Baker
- Section of Clinical Genetics and Metabolism, Department of Pediatrics
| | - Jacob E Friedman
- Section of Neonatology, Department of Pediatrics.,Department of Biochemistry and Molecular Genetics, and.,Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
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Kosmalski M, Mokros Ł, Kuna P, Witusik A, Pietras T. Changes in the immune system - the key to diagnostics and therapy of patients with non-alcoholic fatty liver disease. Cent Eur J Immunol 2018; 43:231-239. [PMID: 30135638 PMCID: PMC6102613 DOI: 10.5114/ceji.2018.77395] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2017] [Accepted: 06/12/2017] [Indexed: 12/13/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the most common pathologies of that organ. The development of the disease involves a variety of mechanisms, including insulin resistance, oxidative stress, endoplasmic reticulum stress, endotoxins from the intestinal flora and genetic predispositions. Additionally, clinical data suggest that the presence of NAFLD is associated with excessive activation of the immune system. For practical purposes, attention should be paid to the moment when the subjects predisposed to NAFLD develop inflammatory infiltration and signs of fibrosis in the liver (non-alcoholic steatohepatitis - NASH). Their presence is an important risk factor for hepatic cirrhosis, hepatic failure, and hepatocellular carcinoma, as well as for the occurrence of cardiovascular events. Regardless of the diagnostic methods used, including laboratory tests and imaging, liver biopsy remains the gold standard to identify and differentiate patients with NAFLD and NASH. The search for other, safer, cheaper and more readily available diagnostic tests is still being continued. Attention has been drawn to the usefulness of markers of immune status of the organism, not only for the diagnosis of NASH, but also for the identification of NAFLD patients at risk of disease progression. Despite the effectiveness of medication, no recommendations have been established for pharmacotherapy of NAFLD. Data indicate the primary need for non-pharmacological interventions to reduce body weight. However, there is evidence of the applicability of certain drugs and dietary supplements, which, by their effect on the immune system, inhibit its excessive activity, thus preventing the progression of NAFLD to NASH.
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Affiliation(s)
- Marcin Kosmalski
- Department of Clinical Pharmacology, Medical University of Lodz, Poland
| | - Łukasz Mokros
- Department of Clinical Pharmacology, Medical University of Lodz, Poland
| | - Piotr Kuna
- Department of Internal Medicine, Asthma and Allergy, Medical University of Lodz, Poland
| | - Andrzej Witusik
- Department of Psychology, Piotrków Trybunalski Branch, Jan Kochanowski University in Kielce, Poland
| | - Tadeusz Pietras
- Department of Clinical Pharmacology, Medical University of Lodz, Poland
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Zhu SY, Jiang N, Yang J, Tu J, Zhou Y, Xiao X, Dong Y. Silybum marianum oil attenuates hepatic steatosis and oxidative stress in high fat diet-fed mice. Biomed Pharmacother 2018; 100:191-197. [PMID: 29428667 DOI: 10.1016/j.biopha.2018.01.144] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 01/08/2018] [Accepted: 01/28/2018] [Indexed: 02/08/2023] Open
Abstract
In the present study, the effects of Silybum marianum oil (SMO) on hepatic steatosis and oxidative stress were investigated during the development of nonalcoholic fatty liver disease (NAFLD) in high fat diet (HFD)-fed mice. The results showed that body weight, fat mass, and serum biochemical parameters such as triglyceride, free fatty acid, glucose and insulin were reduced by SMO treatment. Meanwhile, SMO decreased the histological injury of liver and the levels of hepatic triglyceride, cholesterol and free fatty acid in HFD-fed mice. SMO administration elevated the activities of superoxide dismutase (SOD) and catalase (CAT) and reduced the level of malondialdehyde (MDA) in the liver. Enzyme linked immunosorbent assay showed that SMO significantly decreased the levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in HFD mice. Furthermore, the mRNA levels of sterol regulatory element binding protein 1c (SREBP-1c), fatty acid synthase (FAS) and liver X receptor α (LXRα) were lower, but peroxisome proliferator-activated receptor α (PPARα) was higher in mice treated with SMO compared with the HFD group. The results indicated that SMO could play a certain protective role against HFD-induced NAFLD, and the protective effects might be associated with attenuating lipid accumulation, oxidative stress and inflammation, improving lipid metabolism.
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Affiliation(s)
- Shu Yun Zhu
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China; Jiangsu Hengshun Group Co., Ltd., Zhenjiang 212000, China.
| | - Ning Jiang
- Institute of Vegetables, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
| | - Jing Yang
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China
| | - Jie Tu
- College of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang 212018, China
| | - Yue Zhou
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China
| | - Xiang Xiao
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China
| | - Ying Dong
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China
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Severity of nonalcoholic fatty liver disease is associated with subclinical cerebro-cardiovascular atherosclerosis risk in Korean men. PLoS One 2018; 13:e0193191. [PMID: 29565984 PMCID: PMC5863945 DOI: 10.1371/journal.pone.0193191] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Accepted: 02/06/2018] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND No studies have reported the relationship between nonalcoholic fatty liver disease (NAFLD) and concurrent cerebral artery and coronary artery atherosclerosis simultaneously. We aimed at determining whether NAFLD, as assessed by ultrasound, is associated with subclinical cerebro-cardio vascular atherosclerosis (CCVA) by multidetector-row computed tomography (MDCT), and high resolution-magnetic resonance angiography (HR-MRA). This cross-sectional study included men in the general Korean population aged 20-70 years. RESULTS A total of 1,652 men participated in the study (normal, n = 835; mild-to-moderate NAFLD, n = 512; severe NAFLD, n = 305). The risk of subclinical CCVA was positively associated with age (odds ratio [OR] 1.068; 1.054-1.081, p < 0.001), body mass index (OR 1.120; 1.08 0-1.162, p < 0.001), hepatic enzyme levels (OR 1.012; 1.001-1.023, p = 0.027; OR 1.006; 1.001-1.012, p = 0.036), fasting glucose (OR 1.021; 1.015-1.027, p < 0.001), triglycerides (OR 1.002; 1.000-1.003, p = 0.016), hypertension (OR 2.836; 2.268-3.546, p < 0.001), and diabetes (OR 2.911; 2.137-3.964, p < 0.001). Also, high-density lipoprotein cholesterol was inversely associated with subclinical CCVA (OR 0.974; 0.965-0.982, p < 0.001). Compared with normal controls, the OR for subclinical CCVA after full adjustment was 1.46 in the mild-to-moderate NAFLD group (95% confidence interval [CI]: 1.10 to 1.93) and 2.04 in the severe NAFLD group (95% CI: 1.44 to 2.89). CONCLUSIONS Our data show that NAFLD is common among Korean men, and NAFLD severity on ultrasonography is associated with subclinical CCVA, as assessed by MDCT, and HR-MRA.
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Chella Krishnan K, Kurt Z, Barrere-Cain R, Sabir S, Das A, Floyd R, Vergnes L, Zhao Y, Che N, Charugundla S, Qi H, Zhou Z, Meng Y, Pan C, Seldin MM, Norheim F, Hui S, Reue K, Lusis AJ, Yang X. Integration of Multi-omics Data from Mouse Diversity Panel Highlights Mitochondrial Dysfunction in Non-alcoholic Fatty Liver Disease. Cell Syst 2018; 6:103-115.e7. [PMID: 29361464 DOI: 10.1016/j.cels.2017.12.006] [Citation(s) in RCA: 100] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2017] [Revised: 10/24/2017] [Accepted: 12/08/2017] [Indexed: 12/25/2022]
Abstract
The etiology of non-alcoholic fatty liver disease (NAFLD), the most common form of chronic liver disease, is poorly understood. To understand the causal mechanisms underlying NAFLD, we conducted a multi-omics, multi-tissue integrative study using the Hybrid Mouse Diversity Panel, consisting of ∼100 strains of mice with various degrees of NAFLD. We identified both tissue-specific biological processes and processes that were shared between adipose and liver tissues. We then used gene network modeling to predict candidate regulatory genes of these NAFLD processes, including Fasn, Thrsp, Pklr, and Chchd6. In vivo knockdown experiments of the candidate genes improved both steatosis and insulin resistance. Further in vitro testing demonstrated that downregulation of both Pklr and Chchd6 lowered mitochondrial respiration and led to a shift toward glycolytic metabolism, thus highlighting mitochondria dysfunction as a key mechanistic driver of NAFLD.
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Affiliation(s)
- Karthickeyan Chella Krishnan
- Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Zeyneb Kurt
- Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA
| | - Rio Barrere-Cain
- Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA
| | - Simon Sabir
- Department of Psychology, College of Letters and Science, University of California, Los Angeles, CA, USA
| | - Aditi Das
- Department of Psychology, College of Letters and Science, University of California, Los Angeles, CA, USA
| | - Raquel Floyd
- Department of Microbiology, Immunology and Molecular Genetics, College of Letters and Science, University of California, Los Angeles, CA, USA
| | - Laurent Vergnes
- Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Yuqi Zhao
- Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA
| | - Nam Che
- Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Sarada Charugundla
- Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Hannah Qi
- Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Zhiqiang Zhou
- Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Yonghong Meng
- Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Calvin Pan
- Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Marcus M Seldin
- Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Frode Norheim
- Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Simon Hui
- Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Karen Reue
- Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Aldons J Lusis
- Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; Department of Microbiology, Immunology and Molecular Genetics, College of Letters and Science, University of California, Los Angeles, CA, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
| | - Xia Yang
- Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA; Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, CA, USA.
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44
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Chen C, Liu Q, Liu L, Hu Y, Feng Q. Potential Biological Effects of (-)-Epigallocatechin-3-gallate on the Treatment of Nonalcoholic Fatty Liver Disease. Mol Nutr Food Res 2017; 62. [PMID: 28799714 PMCID: PMC6120134 DOI: 10.1002/mnfr.201700483] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Revised: 07/31/2017] [Indexed: 12/25/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a major health issue throughout the world. However, no validated treatments for NAFLD are currently available. In‐depth studies have demonstrated the efficacy of (‐)‐epigallocatechin‐3‐gallate (EGCG), a main bioactive chemical extracted from green tea, in treating NAFLD. EGCG exhibits multi‐pronged preventive and therapeutic activities, including promoting lipid and glucose metabolism, anti‐lipid peroxidation and anti‐inflammation activities, anti‐fibrosis, and anti‐NAFLD related tumor, thus contributing to the mitigation of NAFLD occurrence and progression. The objectives of this paper are to review and discuss the currently known targets, signaling pathways and roles of EGCG that interfere with NAFLD pathogenesis, then providing additional experimental evidence and the foundation for the further studies and clinical applications of EGCG in the prevention and treatment of NAFLD.
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Affiliation(s)
- Cheng Chen
- Institute of Liver DiseasesShuguang Hospital, Shanghai University of Traditional Chinese MedicineShanghaiChina
| | - Qian Liu
- Institute of Liver DiseasesShuguang Hospital, Shanghai University of Traditional Chinese MedicineShanghaiChina
| | - Lin Liu
- Institute of Liver DiseasesShuguang Hospital, Shanghai University of Traditional Chinese MedicineShanghaiChina
| | - Yi‐yang Hu
- Institute of Liver DiseasesShuguang Hospital, Shanghai University of Traditional Chinese MedicineShanghaiChina
- Shanghai Key Laboratory, Traditional Chinese Clinical MedicineShanghaiChina
- E‐Institute of Shanghai Municipal Education CommitteeShanghaiChina
| | - Qin Feng
- Institute of Liver DiseasesShuguang Hospital, Shanghai University of Traditional Chinese MedicineShanghaiChina
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Lou Z, Xia B, Su J, Yu J, Yan M, Huang Y, Lv G. Effect of a stilbene glycoside-rich extract from Polygoni Multiflori Radix on experimental non-alcoholic fatty liver disease based on principal component and orthogonal partial least squares discriminant analysis. Exp Ther Med 2017; 14:4958-4966. [PMID: 29201200 PMCID: PMC5704276 DOI: 10.3892/etm.2017.5197] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2016] [Accepted: 07/07/2017] [Indexed: 12/18/2022] Open
Abstract
Polygoni Multiflori Radix is a traditional Chinese medicine used clinically to support the functions of the liver and kidneys and to treatment hyperlipidemia. In previous studies, an effective fraction, rich in 2,3,5,4′-tetrahydroxy stilbene-2-O-β-D-glucoside (TSG), was separated from Polygoni Multiflori Radix and demonstrated hypolipidemic activity. The present study aimed to systematically assess the effect of this fraction on non-alcoholic fatty liver disease (NAFLD). A NAFLD model was established by feeding Sprague-Dawley rats a high-fat diet with 10% fructose solution for 18 weeks. Hematoxylin and eosin staining was applied for hepatic histopathological analysis. In addition, enzyme activities, lipid metabolism, inflammatory factors and insulin resistance indices were measured using a fully automatic blood biochemistry analyser and ELISA. Furthermore, cytochrome P450 2E1 (CYP2E1) and peroxisome proliferator-activated receptor α (PPARα) mRNA and protein expression were evaluated using reverse transcription-quantitative polymerase chain reaction and western blot analysis. Principal component analysis and orthogonal partial least squares discriminant analysis were used to analyse the data. The results revealed that the TSG-rich fraction (TSGP) significantly lowered the serum total cholesterol and triglyceride levels, and the liver free fatty acid, CYP2E1 mRNA and malondialdehyde levels, in addition to mitigating hepatic enlargement and alleviating liver steatosis. Furthermore, it upregulated PPARα mRNA expression in the liver tissue. The results indicated that TSGP exhibited a protective effect against NAFLD and the underlying mechanism may involve augmentation of anti-lipid peroxidation capacity via regulation of PPARα and CYP2E1-mediated pathways.
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Affiliation(s)
- Zhaohuan Lou
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China.,Zhejiang Provincial Key Laboratory of Pharmacological Research of TCM on Hypertension and Related Diseases, Hangzhou, Zhejiang 315053, P.R. China
| | - Bohou Xia
- College of Pharmaceutical Science, Hunan University of Chinese Medicine, Changsha, Hunan 410208, P.R. China
| | - Jie Su
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China.,Zhejiang Provincial Key Laboratory of Pharmacological Research of TCM on Hypertension and Related Diseases, Hangzhou, Zhejiang 315053, P.R. China
| | - Jingjing Yu
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China.,Zhejiang Provincial Key Laboratory of Pharmacological Research of TCM on Hypertension and Related Diseases, Hangzhou, Zhejiang 315053, P.R. China
| | - Meiqiu Yan
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China.,Zhejiang Provincial Key Laboratory of Pharmacological Research of TCM on Hypertension and Related Diseases, Hangzhou, Zhejiang 315053, P.R. China
| | - Yuefang Huang
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
| | - Guiyuan Lv
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China.,Zhejiang Provincial Key Laboratory of Pharmacological Research of TCM on Hypertension and Related Diseases, Hangzhou, Zhejiang 315053, P.R. China
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Antihyperlipidaemic and hepatoprotective activities of acidic and enzymatic hydrolysis exopolysaccharides from Pleurotus eryngii SI-04. Altern Ther Health Med 2017; 17:403. [PMID: 28806986 PMCID: PMC5557422 DOI: 10.1186/s12906-017-1892-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Accepted: 07/26/2017] [Indexed: 12/23/2022]
Abstract
Background Hyperlipidaemia is the major risk factor contributing to the development and progression of atherosclerosis, fatty liver and cerebrovascular disease. Pleurotus eryngii (P. eryngii) is rich in biologically active components, especially polysaccharides that exhibit various biological activities, including reducing blood lipids. In the present study, three novel polysaccharide types, including exopolysaccharides (EPS), enzymatic EPS (EEPS) and acidic EPS (AEPS) were isolated, and the hypolipidaemic and hepatoprotective effects were investigated to better understand possible hypolipidaemic mechanisms and their hepatoprotective effects. Methods The EPS was hydrolysed by snailase (dissolved in 1% acetic acid, pH = 6) and H2SO4 (1 M) to obtain EEPS and AEPS, respectively. The in vitro antioxidant activities were measured by investigating the reducing power and the scavenging effects on radicals of hydroxyl, 1,1-diphenyl-2-picrylhydrazyl (DPPH) and superoxide anion. The hyperlipidaemic mice were induced by perfusing a high-fat emulsion. In addition to the hepatic histopathology, the following biochemical analyses were performed to investigate the antioxidative effects, including the activities of alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and catalase (CAT). Triacylglycerol (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), malondialdehyde (MDA) and lipid peroxidation (LPO) levels were also measured in serum and liver homogenate. Results Supplementation of EPS, EEPS and AEPS could significantly improve blood lipid levels (TC, TG, HDL-C, and LDL-C), hepatic lipid levels (TC and TG), hepatic enzyme activities (ALP, ALT, and AST) and antioxidant status (GSH-Px, SOD, T-AOC, MDA, and LPO). In addition, histopathological observations indicated that these polysaccharides had potential effects in attenuating hepatocyte damage. Conclusion These results demonstrated that both EPS and its hydrolysates EEPS and AEPS might effectively reduce serum lipid levels and protect against high-fat diet-induced hyperlipidaemia, indicating that they could be used as functional foods and natural hepatoprotectants.
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Li G, Zhou F, Chen Y, Zhang W, Wang N. Kukoamine A attenuates insulin resistance and fatty liver through downregulation of Srebp-1c. Biomed Pharmacother 2017; 89:536-543. [PMID: 28254666 DOI: 10.1016/j.biopha.2017.02.024] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Revised: 02/06/2017] [Accepted: 02/08/2017] [Indexed: 01/17/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) refers to a pathological condition of hepatic steatosis. Insulin resistance is believed to be the key mechanism mediating initial accumulation of fat in the liver, resulting in hepatic steatosis. Kukoamine A (KuA), a spermine alkaloid, is a major bioactive component extracted from the root barks of Lycium chinense (L. chinense) Miller. In the current study, we aimed to explore the possible effect of KuA on insulin resistance and fatty liver. We showed that KuA significantly inhibited the increase of fasting blood glucose level and insulin level, and the glucose levels in response to glucose and insulin load in HFD-fed mice, which was in a dose-dependent manner. KuA dose-dependently decreased the histological injury of liver, levels of hepatic triglyceride (TG), and serum AST and ALT activities in HFD-fed mice. The increase of serum levels of TNFɑ, IL-1β, IL-6 and C reactive protein in HFD-fed mice was inhibited by KuA. HFD feeding-induced increase of hepatic expression of Srebp-1c and its target genes, including fatty acid synthase (FAS) and acetyl CoA carboxylase 1 (ACC1), was significantly inhibited by KuA. Moreover, upregulation of Srebp-1c notably inhibited KuA-induced improvement of insulin-stimulated glucose uptake, decrease of lipid accumulation and H2O2 level in palmitic acid-treated AML-12 cells. In conclusion, we reported that KuA inhibited Srebp-1c and downstream genes expression and resulted in inhibition of lipid accumulation, inflammation, insulin resistance and oxidative stress. Overall, our results provide a better understanding of the pharmacological activities of KuA against insulin resistance and hepatic steatosis.
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Affiliation(s)
- Guangyun Li
- Department of Pharmacy, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan, China.
| | - Fang Zhou
- Department of Pharmacy, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan, China
| | - Ying Chen
- Department of Pharmacy, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan, China
| | - Weiguo Zhang
- Department of Pharmacy, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan, China
| | - Ning Wang
- Department of Pharmacy, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan, China
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48
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The Role of Fructose, and Specifically Sugar-Sweetened Beverages, in Pediatric Nonalcoholic Fatty Liver Disease. TOP CLIN NUTR 2017. [DOI: 10.1097/tin.0000000000000091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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49
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Walenbergh SMA, Houben T, Rensen SS, Bieghs V, Hendrikx T, van Gorp PJ, Oligschlaeger Y, Jeurissen MLJ, Gijbels MJJ, Buurman WA, Vreugdenhil ACE, Greve JWM, Plat J, Hofker MH, Kalhan S, Pihlajamäki J, Lindsey P, Koek GH, Shiri-Sverdlov R. Plasma cathepsin D correlates with histological classifications of fatty liver disease in adults and responds to intervention. Sci Rep 2016; 6:38278. [PMID: 27922112 PMCID: PMC5138820 DOI: 10.1038/srep38278] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Accepted: 10/25/2016] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is characterized by liver lipid accumulation and inflammation. The mechanisms that trigger hepatic inflammation are poorly understood and subsequently, no specific non-invasive markers exist. We previously demonstrated a reduction in the plasma lysosomal enzyme, cathepsin D (CatD), in children with NASH compared to children without NASH. Recent studies have raised the concept that non-alcoholic fatty liver disease (NAFLD) in adults is distinct from children due to a different histological pattern in the liver. Yet, the link between plasma CatD to adult NASH was not examined. In the current manuscript, we investigated whether plasma CatD in adults correlates with NASH development and regression. Biopsies were histologically evaluated for inflammation and NAFLD in three complementary cohorts of adults (total n = 248). CatD and alanine aminotransferase (ALT) were measured in plasma. Opposite to our previous observations with childhood NASH, we observed increased levels of plasma CatD in patients with NASH compared to adults without hepatic inflammation. Furthermore, after surgical intervention, we found a reduction of plasma CatD compared to baseline. Our observations highlight a distinct pathophysiology between NASH in children and adults. The observation that plasma CatD correlated with NASH development and regression is promising for NASH diagnosis.
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Affiliation(s)
- Sofie M A Walenbergh
- Molecular Genetics, General Surgery, Paediatrics, Pathology, Population Genetics, Human Biology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
| | - Tom Houben
- Molecular Genetics, General Surgery, Paediatrics, Pathology, Population Genetics, Human Biology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
| | - Sander S Rensen
- Molecular Genetics, General Surgery, Paediatrics, Pathology, Population Genetics, Human Biology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
| | - Veerle Bieghs
- Molecular Genetics, General Surgery, Paediatrics, Pathology, Population Genetics, Human Biology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
| | - Tim Hendrikx
- Molecular Genetics, General Surgery, Paediatrics, Pathology, Population Genetics, Human Biology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
| | - Patrick J van Gorp
- Molecular Genetics, General Surgery, Paediatrics, Pathology, Population Genetics, Human Biology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
| | - Yvonne Oligschlaeger
- Molecular Genetics, General Surgery, Paediatrics, Pathology, Population Genetics, Human Biology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
| | - Mike L J Jeurissen
- Molecular Genetics, General Surgery, Paediatrics, Pathology, Population Genetics, Human Biology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
| | - Marion J J Gijbels
- Molecular Genetics, General Surgery, Paediatrics, Pathology, Population Genetics, Human Biology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
| | - Wim A Buurman
- Molecular Genetics, General Surgery, Paediatrics, Pathology, Population Genetics, Human Biology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
| | - Anita C E Vreugdenhil
- Molecular Genetics, General Surgery, Paediatrics, Pathology, Population Genetics, Human Biology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
| | - Jan Willem M Greve
- Surgery, Atrium Medical Center Parkstad, 6419PC, Heerlen, The Netherlands
| | - Jogchum Plat
- Molecular Genetics, General Surgery, Paediatrics, Pathology, Population Genetics, Human Biology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
| | - Marten H Hofker
- Pathology and Medical Biology, Molecular Genetics, Medical Biology Section, University Medical Center Groningen, 9713GZ, Groningen, The Netherlands
| | - Satish Kalhan
- Pathobiology, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, USA
| | - Jussi Pihlajamäki
- Clinical Nutrition, University of Eastern Finland, FI-70211 Kuopio, Finland.,Clinical Nutrition and Obesity Center, Kuopio University Hospital, FI-70211 Kuopio, Finland
| | - Patrick Lindsey
- Molecular Genetics, General Surgery, Paediatrics, Pathology, Population Genetics, Human Biology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
| | - Ger H Koek
- Internal Medicine, Division of Gastroenterology and Hepatology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
| | - Ronit Shiri-Sverdlov
- Molecular Genetics, General Surgery, Paediatrics, Pathology, Population Genetics, Human Biology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
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Jeurissen MLJ, Walenbergh SMA, Houben T, Hendrikx T, Li J, Oligschlaeger Y, van Gorp PJ, Gijbels MJJ, Bitorina A, Nessel I, Radtke F, Vooijs M, Theys J, Shiri-Sverdlov R. Myeloid DLL4 Does Not Contribute to the Pathogenesis of Non-Alcoholic Steatohepatitis in Ldlr-/- Mice. PLoS One 2016; 11:e0167199. [PMID: 27898698 PMCID: PMC5127569 DOI: 10.1371/journal.pone.0167199] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Accepted: 11/10/2016] [Indexed: 01/17/2023] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is characterized by liver steatosis and inflammation. Currently, the underlying mechanisms leading to hepatic inflammation are not fully understood and consequently, therapeutic options are poor. Non-alcoholic steatohepatitis (NASH) and atherosclerosis share the same etiology whereby macrophages play a key role in disease progression. Macrophage function can be modulated via activation of receptor-ligand binding of Notch signaling. Relevantly, global inhibition of Notch ligand Delta-Like Ligand-4 (DLL4) attenuates atherosclerosis by altering the macrophage-mediated inflammatory response. However, the specific contribution of macrophage DLL4 to hepatic inflammation is currently unknown. We hypothesized that myeloid DLL4 deficiency in low-density lipoprotein receptor knock-out (Ldlr-/-) mice reduces hepatic inflammation. Irradiated Ldlr-/- mice were transplanted (tp) with bone marrow from wild type (Wt) or DLL4f/fLysMCre+/0 (DLL4del) mice and fed either chow or high fat, high cholesterol (HFC) diet for 11 weeks. Additionally, gene expression was assessed in bone marrow-derived macrophages (BMDM) of DLL4f/fLysMCreWT and DLL4f/fLysMCre+/0 mice. In contrast to our hypothesis, inflammation was not decreased in HFC-fed DLL4del-transplanted mice. In line, in vitro, there was no difference in the expression of inflammatory genes between DLL4-deficient and wildtype bone marrow-derived macrophages. These results suggest that myeloid DLL4 deficiency does not contribute to hepatic inflammation in vivo. Since, macrophage-DLL4 expression in our model was not completely suppressed, it can’t be totally excluded that complete DLL4 deletion in macrophages might lead to different results. Nevertheless, the contribution of non-myeloid Kupffer cells to notch signaling with regard to the pathogenesis of steatohepatitis is unknown and as such it is possible that, DLL4 on Kupffer cells promote the pathogenesis of steatohepatitis.
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Affiliation(s)
- Mike L. J. Jeurissen
- Departments of Molecular Genetics, Pathology and Radiotherapy, School of Nutrition and Translational Research in Metabolism (NUTRIM), School for Cardiovascular Diseases (CARIM) and MAASTRO/School for Developmental Biology & Oncology (GROW), Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - Sofie M. A. Walenbergh
- Departments of Molecular Genetics, Pathology and Radiotherapy, School of Nutrition and Translational Research in Metabolism (NUTRIM), School for Cardiovascular Diseases (CARIM) and MAASTRO/School for Developmental Biology & Oncology (GROW), Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - Tom Houben
- Departments of Molecular Genetics, Pathology and Radiotherapy, School of Nutrition and Translational Research in Metabolism (NUTRIM), School for Cardiovascular Diseases (CARIM) and MAASTRO/School for Developmental Biology & Oncology (GROW), Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - Tim Hendrikx
- Departments of Molecular Genetics, Pathology and Radiotherapy, School of Nutrition and Translational Research in Metabolism (NUTRIM), School for Cardiovascular Diseases (CARIM) and MAASTRO/School for Developmental Biology & Oncology (GROW), Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - Jieyi Li
- Departments of Molecular Genetics, Pathology and Radiotherapy, School of Nutrition and Translational Research in Metabolism (NUTRIM), School for Cardiovascular Diseases (CARIM) and MAASTRO/School for Developmental Biology & Oncology (GROW), Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - Yvonne Oligschlaeger
- Departments of Molecular Genetics, Pathology and Radiotherapy, School of Nutrition and Translational Research in Metabolism (NUTRIM), School for Cardiovascular Diseases (CARIM) and MAASTRO/School for Developmental Biology & Oncology (GROW), Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - Patrick J. van Gorp
- Departments of Molecular Genetics, Pathology and Radiotherapy, School of Nutrition and Translational Research in Metabolism (NUTRIM), School for Cardiovascular Diseases (CARIM) and MAASTRO/School for Developmental Biology & Oncology (GROW), Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - Marion J. J. Gijbels
- Departments of Molecular Genetics, Pathology and Radiotherapy, School of Nutrition and Translational Research in Metabolism (NUTRIM), School for Cardiovascular Diseases (CARIM) and MAASTRO/School for Developmental Biology & Oncology (GROW), Maastricht University Medical Centre+, Maastricht, The Netherlands
- Experimental Vascular Biology, Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Albert Bitorina
- Departments of Molecular Genetics, Pathology and Radiotherapy, School of Nutrition and Translational Research in Metabolism (NUTRIM), School for Cardiovascular Diseases (CARIM) and MAASTRO/School for Developmental Biology & Oncology (GROW), Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - Isabell Nessel
- Departments of Molecular Genetics, Pathology and Radiotherapy, School of Nutrition and Translational Research in Metabolism (NUTRIM), School for Cardiovascular Diseases (CARIM) and MAASTRO/School for Developmental Biology & Oncology (GROW), Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - Freddy Radtke
- Ecole Polytechnique Fédérale de Lausanne, School of Life Sciences, Swiss Experimental Cancer Research Institute, Lausanne, Switzerland
| | - Marc Vooijs
- Departments of Molecular Genetics, Pathology and Radiotherapy, School of Nutrition and Translational Research in Metabolism (NUTRIM), School for Cardiovascular Diseases (CARIM) and MAASTRO/School for Developmental Biology & Oncology (GROW), Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - Jan Theys
- Departments of Molecular Genetics, Pathology and Radiotherapy, School of Nutrition and Translational Research in Metabolism (NUTRIM), School for Cardiovascular Diseases (CARIM) and MAASTRO/School for Developmental Biology & Oncology (GROW), Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - Ronit Shiri-Sverdlov
- Departments of Molecular Genetics, Pathology and Radiotherapy, School of Nutrition and Translational Research in Metabolism (NUTRIM), School for Cardiovascular Diseases (CARIM) and MAASTRO/School for Developmental Biology & Oncology (GROW), Maastricht University Medical Centre+, Maastricht, The Netherlands
- * E-mail:
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