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Wang YH, Chung CH, Huang TY, Chang CF, Yang CW, Chien WC, Cheng YC. Association between nonalcoholic fatty liver disease and incidence of inflammatory bowel disease: a nationwide population‑based cohort study. Intest Res 2025; 23:76-84. [PMID: 38373704 PMCID: PMC11834356 DOI: 10.5217/ir.2023.00078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 12/07/2023] [Accepted: 12/22/2023] [Indexed: 02/21/2024] Open
Abstract
BACKGROUND/AIMS Nonalcoholic fatty liver disease (NAFLD) is a common disease with severe inflammatory processes associated with numerous gastrointestinal diseases, such as inflammatory bowel disease (IBD). Therefore, we investigated the relationship between NAFLD and IBD and the possible risk factors associated with the diagnosis of IBD. METHODS This longitudinal nationwide cohort study investigated the risk of IBD in patients with NAFLD alone. General characteristics, comorbidities, and incidence of IBD were also compared. RESULTS Patients diagnosed with NAFLD had a significant risk of developing IBD compared to control individuals, who were associated with a 2.245-fold risk of the diagnosis of IBD and a 2.260- and 2.231-fold of increased diagnosis of ulcerative colitis and Crohn's disease, respectively (P< 0.001). The cumulative risk of IBD increased annually during the follow-up of patients with NAFLD (P< 0.001). CONCLUSIONS Our results emphasize that NAFLD significantly impacts its incidence in patients with NAFLD. If patients with NAFLD present with risk factors, such as diabetes mellitus and dyslipidemia, these conditions should be properly treated with regular follow-ups. Furthermore, we believe that these causes may be associated with the second peak of IBD.
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Affiliation(s)
- Ying-Hsiang Wang
- Division of Colon and Rectal Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Chi-Hsiang Chung
- School of Public Health, National Defense Medical Center, Taipei, Taiwan
| | - Tien-Yu Huang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Chao-Feng Chang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Chi-Wei Yang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Wu-Chien Chien
- School of Public Health, National Defense Medical Center, Taipei, Taiwan
- Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Yi-Chiao Cheng
- Division of Colon and Rectal Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
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Diwan R, Gaytan SL, Bhatt HN, Pena-Zacarias J, Nurunnabi M. Liver fibrosis pathologies and potentials of RNA based therapeutics modalities. Drug Deliv Transl Res 2024; 14:2743-2770. [PMID: 38446352 DOI: 10.1007/s13346-024-01551-8] [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] [Accepted: 02/14/2024] [Indexed: 03/07/2024]
Abstract
Liver fibrosis (LF) occurs when the liver tissue responds to injury or inflammation by producing excessive amounts of scar tissue, known as the extracellular matrix. This buildup stiffens the liver tissue, hinders blood flow, and ultimately impairs liver function. Various factors can trigger this process, including bloodborne pathogens, genetic predisposition, alcohol abuse, non-steroidal anti-inflammatory drugs, non-alcoholic steatohepatitis, and non-alcoholic fatty liver disease. While some existing small-molecule therapies offer limited benefits, there is a pressing need for more effective treatments that can truly cure LF. RNA therapeutics have emerged as a promising approach, as they can potentially downregulate cytokine levels in cells responsible for liver fibrosis. Researchers are actively exploring various RNA-based therapeutics, such as mRNA, siRNA, miRNA, lncRNA, and oligonucleotides, to assess their efficacy in animal models. Furthermore, targeted drug delivery systems hold immense potential in this field. By utilizing lipid nanoparticles, exosomes, nanocomplexes, micelles, and polymeric nanoparticles, researchers aim to deliver therapeutic agents directly to specific biomarkers or cytokines within the fibrotic liver, increasing their effectiveness and reducing side effects. In conclusion, this review highlights the complex nature of liver fibrosis, its underlying causes, and the promising potential of RNA-based therapeutics and targeted delivery systems. Continued research in these areas could lead to the development of more effective and personalized treatment options for LF patients.
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Affiliation(s)
- Rimpy Diwan
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Texas El Paso, El Paso, TX, 79902, USA
- Department of Biomedical Engineering, College of Engineering, The University of Texas El Paso, El Paso, TX, 79968, USA
| | - Samantha Lynn Gaytan
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Texas El Paso, El Paso, TX, 79902, USA
- Department of Interdisciplinary Health Sciences, College of Health Sciences, The University of Texas El Paso, El Paso, Texas, 79968, USA
| | - Himanshu Narendrakumar Bhatt
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Texas El Paso, El Paso, TX, 79902, USA
- Department of Biomedical Engineering, College of Engineering, The University of Texas El Paso, El Paso, TX, 79968, USA
| | - Jacqueline Pena-Zacarias
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Texas El Paso, El Paso, TX, 79902, USA
- Department of Biological Sciences, College of Science, The University of Texas El Paso, El Paso, Texas, 79968, USA
| | - Md Nurunnabi
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Texas El Paso, El Paso, TX, 79902, USA.
- Department of Biomedical Engineering, College of Engineering, The University of Texas El Paso, El Paso, TX, 79968, USA.
- Department of Interdisciplinary Health Sciences, College of Health Sciences, The University of Texas El Paso, El Paso, Texas, 79968, USA.
- Border Biomedical Research Center, The University of Texas El Paso, El Paso, TX, 79968, USA.
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Kang SA, Yu HS. Anti-obesity effects by parasitic nematode ( Trichinella spiralis) total lysates. Front Cell Infect Microbiol 2024; 13:1285584. [PMID: 38259965 PMCID: PMC10800963 DOI: 10.3389/fcimb.2023.1285584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 12/11/2023] [Indexed: 01/24/2024] Open
Abstract
Background Obesity is an inducible factor for the cause of chronic diseases and is described by an increase in the size and number of adipocytes that differentiate from precursor cells (preadipocytes). Parasitic helminths are the strongest natural trigger of type 2 immune system, and several studies have showed that helminth infections are inversely correlated with metabolic syndromes. Methodology/Principal findings To investigate whether helminth-derived molecules have therapeutic effects on high-fat diet (HFD)-induced obesity, we isolated total lysates from Trichinella spiralis muscle larvae. We then checked the anti-obesity effect after intraperitoneal administration and intraoral administration of total lysate from T. spiralis muscle larvae in a diet-induced obesity model. T. spiralis total lysates protect against obesity by inhibiting the proinflammatory response and/or enhancing M2 macrophages. In addition, we determined the effects of total lysates from T. spiralis muscle larvae on anti-obesity activities in 3T3-L1 preadipocytes by investigating the expression levels of key adipogenic regulators, including peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT-enhancer-binding protein alpha (C/EBPα) and adipocyte protein 2 (aP2). Oil Red O staining showed that the total lysates from T. spiralis muscle larvae decreased the differentiation of 3T3-L1 preadipocytes by decreasing the number of lipid droplets. In addition, the production levels of proinflammatory cytokines IL-1β, IL-6, IFN-γ and TNF-α were examined by enzyme-linked immunosorbent assay (ELISA). T. spiralis total lysates decreased intracellular lipid accumulation and suppressed the expression levels of PPARγ, C/EBPα and aP2. Conclusion/Significance These results show that T. spiralis total lysate significantly suppresses the symptoms of obesity in a diet- induced obesity model and 3T3-L1 cell differentiation and suggest that it has potential for novel anti-obesity therapeutics.
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Affiliation(s)
- Shin Ae Kang
- Department of Parasitology and Tropical Medicine, School of Medicine, Pusan National University, Yangsan, Republic of Korea
| | - Hak Sun Yu
- Department of Parasitology and Tropical Medicine, School of Medicine, Pusan National University, Yangsan, Republic of Korea
- Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea
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Engin A. Nonalcoholic Fatty Liver Disease and Staging of Hepatic Fibrosis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:539-574. [PMID: 39287864 DOI: 10.1007/978-3-031-63657-8_18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is in parallel with the obesity epidemic, and it is the most common cause of liver diseases. The patients with severe insulin-resistant diabetes having high body mass index (BMI), high-grade adipose tissue insulin resistance, and high hepatocellular triacylglycerols (triglycerides; TAG) content develop hepatic fibrosis within a 5-year follow-up. Insulin resistance with the deficiency of insulin receptor substrate-2 (IRS-2)-associated phosphatidylinositol 3-kinase (PI3K) activity causes an increase in intracellular fatty acid-derived metabolites such as diacylglycerol (DAG), fatty acyl CoA, or ceramides. Lipotoxicity-related mechanism of NAFLD could be explained still best by the "double-hit" hypothesis. Insulin resistance is the major mechanism in the development and progression of NAFLD/nonalcoholic steatohepatitis (NASH). Metabolic oxidative stress, autophagy, and inflammation induce NASH progression. In the "first hit" the hepatic concentrations of diacylglycerol increase with an increase in saturated liver fat content in human NAFLD. Activities of mitochondrial respiratory chain complexes are decreased in the liver tissue of patients with NASH. Hepatocyte lipoapoptosis is a critical feature of NASH. In the "second hit," reduced glutathione levels due to oxidative stress lead to the overactivation of c-Jun N-terminal kinase (JNK)/c-Jun signaling that induces cell death in the steatotic liver. Accumulation of toxic levels of reactive oxygen species (ROS) is caused at least by two ineffectual cyclical pathways. First is the endoplasmic reticulum (ER) oxidoreductin (Ero1)-protein disulfide isomerase oxidation cycle through the downstream of the inner membrane mitochondrial oxidative metabolism and the second is the Kelch like-ECH-associated protein 1 (Keap1)-nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathways. In clinical practice, on ultrasonographic examination, the elevation of transaminases, γ-glutamyltransferase, and the aspartate transaminase to platelet ratio index indicates NAFLD. Fibrosis-4 index, NAFLD fibrosis score, and cytokeratin18 are used for grading steatosis, staging fibrosis, and discriminating the NASH from simple steatosis, respectively. In addition to ultrasonography, "controlled attenuation parameter," "magnetic resonance imaging proton-density fat fraction," "ultrasound-based elastography," "magnetic resonance elastography," "acoustic radiation force impulse elastography imaging," "two-dimensional shear-wave elastography with supersonic imagine," and "vibration-controlled transient elastography" are recommended as combined tests with serum markers in the clinical evaluation of NAFLD. However, to confirm the diagnosis of NAFLD, a liver biopsy is the gold standard. Insulin resistance-associated hyperinsulinemia directly accelerates fibrogenesis during NAFLD development. Although hepatocyte lipoapoptosis is a key driving force of fibrosis progression, hepatic stellate cells and extracellular matrix cells are major fibrogenic effectors. Thereby, these are pharmacological targets of therapies in developing hepatic fibrosis. Nonpharmacological management of NAFLD mainly consists of two alternatives: lifestyle modification and metabolic surgery. Many pharmacological agents that are thought to be effective in the treatment of NAFLD have been tried, but due to lack of ability to attenuate NAFLD, or adverse effects during the phase trials, the vast majority could not be licensed.
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Affiliation(s)
- Atilla Engin
- Faculty of Medicine, Department of General Surgery, Gazi University, Besevler, Ankara, Turkey.
- Mustafa Kemal Mah. 2137. Sok. 8/14, 06520, Cankaya, Ankara, Turkey.
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Stine JG, Long MT, Corey KE, Sallis RE, Allen AM, Armstrong MJ, Conroy DE, Cuthbertson DJ, Duarte-Rojo A, Hallsworth K, Hickman IJ, Kappus MR, Keating SE, Pugh CJA, Rotman Y, Simon TL, Vilar-Gomez E, Wai-Sun Wong V, Schmitz KH. Physical Activity and Nonalcoholic Fatty Liver Disease: A Roundtable Statement from the American College of Sports Medicine. Med Sci Sports Exerc 2023; 55:1717-1726. [PMID: 37126039 PMCID: PMC10524517 DOI: 10.1249/mss.0000000000003199] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/02/2023]
Abstract
ABSTRACT Although physical activity (PA) is crucial in the prevention and clinical management of nonalcoholic fatty liver disease, most individuals with this chronic disease are inactive and do not achieve recommended amounts of PA. There is a robust and consistent body of evidence highlighting the benefit of participating in regular PA, including a reduction in liver fat and improvement in body composition, cardiorespiratory fitness, vascular biology, and health-related quality of life. Importantly, the benefits of regular PA can be seen without clinically significant weight loss. At least 150 min of moderate or 75 min of vigorous intensity PA are recommended weekly for all patients with nonalcoholic fatty liver disease, including those with compensated cirrhosis. If a formal exercise training program is prescribed, aerobic exercise with the addition of resistance training is preferred. In this roundtable document, the benefits of PA are discussed, along with recommendations for 1) PA assessment and screening; 2) how best to advise, counsel, and prescribe regular PA; and 3) when to refer to an exercise specialist.
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Affiliation(s)
- Jonathan G. Stine
- Division of Gastroenterology and Hepatology, Department of Medicine, The Pennsylvania State University- Milton S. Hershey Medical Center, Hershey PA
- Department of Public Health Sciences, The Pennsylvania State University- College of Medicine, Hershey PA
| | - Michelle T. Long
- Section of Gastroenterology, Evans Department of Medicine, Boston University School of Medicine, Boston, MA
| | - Kathleen E. Corey
- Division of Gastroenterology and Hepatology, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Robert E. Sallis
- Department of Family Medicine and Sports Medicine, Kaiser Permanente Medical Center, Fontana, CA
| | - Alina M. Allen
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN
| | - Matthew J. Armstrong
- Liver Transplant Unit, Queen Elizabeth University Hospitals Birmingham, and NIHR Birmingham Biomedical Research Centre, Birmingham, UNITED KINGDOM
| | - David E. Conroy
- Department of Kinesiology, The Pennsylvania State University, University Park, PA
| | - Daniel J. Cuthbertson
- Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UNITED KINGDOM
| | - Andres Duarte-Rojo
- Division of Gastroenterology and Hepatology, Department of Medicine, Northwestern University, Chicago, IL
| | - Kate Hallsworth
- Newcastle NIHR Biomedical Research Centre and the Liver Unit, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UNITED KINGDOM
| | - Ingrid J. Hickman
- Department of Nutrition and Dietetics, Princess Alexandra Hospital, Brisbane, Queensland, AUSTRALIA
| | - Matthew R. Kappus
- Division of Gastroenterology and Hepatology, Duke University, Durham, NC
| | - Shelley E. Keating
- School of Human Movement and Nutrition Sciences, The University of Queensland, St Lucia, Queensland, AUSTRALIA
| | - Christopher J. A. Pugh
- Cardiff School of Sport & Health Sciences, Cardiff Metropolitan University, Cardiff, UNITED KINGDOM
| | - Yaron Rotman
- Liver & Energy Metabolism Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - Tracey L. Simon
- Division of Gastroenterology and Hepatology, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Eduardo Vilar-Gomez
- Division of Gastroenterology and Hepatology. Indiana University School of Medicine. Indianapolis
| | - Vincent Wai-Sun Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, CHINA
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Sun J, Jin X, Zhang X, Zhang B. HMGA2 knockdown alleviates the progression of nonalcoholic fatty liver disease (NAFLD) by downregulating SNAI2 expression. Cell Signal 2023:110741. [PMID: 37268162 DOI: 10.1016/j.cellsig.2023.110741] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 05/23/2023] [Accepted: 05/28/2023] [Indexed: 06/04/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a complex disease that is considered as the next major health epidemic with alarmingly increasing global prevalence. To explore the pathogenesis of NAFLD, data from GSE118892 were analyzed. High mobility group AT-hook 2 (HMGA2), a member of the high mobility group family, is declined in liver tissues of NAFLD rats. However, its role in NAFLD remains unknown. This study attempted to identify the multiple roles of HMGA2 in NAFLD process. NAFLD was induced in rats using a high-fat diet (HFD). In vivo, HMGA2 knockdown using adenovirus system attenuated liver injury and liver lipid deposition, accompanied by decreased NAFLD score, increased liver function, and decreased CD36 and FAS, indicating the deceleration of NAFLD progression. Moreover, HMGA2 knockdown restrained liver inflammation by decreasing the expression of related inflammatory factors. Importantly, HMGA2 knockdown attenuated liver fibrosis via downregulating the expression of fibrous proteins, and inhibiting the activation of TGF-β1/SMAD signaling pathway. In vitro, HMGA2 knockdown relieved palmitic acid (PA)-induced hepatocyte injury and attenuated TGF-β1-induced liver fibrosis, consistent with in vivo findings. Strikingly, HMGA2 activated the transcription of SNAI2, which was evidenced by the dual luciferase assays. Moreover, HMGA2 knockdown largely downregulated SNAI2 levels. Indeed, SNAI2 overexpression effectively blocked the inhibitory effect of HMGA2 knockdown on NAFLD. Totally, our findings reveal that HMGA2 knockdown alleviates the progression of NAFLD by directly regulating the transcription of SNAI2. HMGA2 inhibition may emerge as a potential therapeutic target for NAFLD.
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Affiliation(s)
- Jing Sun
- Department of Gastroenterology, the First Hospital of China Medical University, Shenyang, Liaoning Province, People's Republic of China.
| | - Xiuli Jin
- Department of Gastroenterology, the First Hospital of China Medical University, Shenyang, Liaoning Province, People's Republic of China
| | - Xinhe Zhang
- Department of Gastroenterology, the First Hospital of China Medical University, Shenyang, Liaoning Province, People's Republic of China
| | - Birong Zhang
- Systems Immunity Research Institute, Cardiff University School of Medicine, Cardiff University, Cardiff, UK
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Xie P, Xie JB, Xiao MY, Guo M, Qi YS, Li FF, Piao XL. Liver lipidomics analysis reveals the anti-obesity and lipid-lowering effects of gypnosides from heat-processed Gynostemma pentaphyllum in high-fat diet fed mice. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 115:154834. [PMID: 37094422 DOI: 10.1016/j.phymed.2023.154834] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 04/02/2023] [Accepted: 04/16/2023] [Indexed: 05/03/2023]
Abstract
BACKGROUND In traditional Chinese medicine, Gynostemma pentaphyllum (G. pentaphyllum) is widely used to treat conditions associated with hyperlipidemia, and its therapeutic potential has been demonstrated in numerous studies. However, the mechanism of lipid metabolism in hyperlipidemic by G. pentaphyllum, especially heat-processed G. pentaphyllum is not yet clear. PURPOSE The aim of this study was to investigate the therapeutic mechanism of gypenosides from heat-processed G. pentaphyllum (HGyp) in hyperlipidemic mice by means of a lipidomics. METHODS The content of the major components of HGyp was determined by ultra-performance liquid chromatography-electrospray ionization ion trap mass spectrometry (UPLC-ESI-MS). An animal model of hyperlipidaemia was constructed using C57BL/6J mice fed with high-fat diet. HGyp was also administered at doses of 50, 100 and 200 mg/kg, all for 12 weeks. Serum parameters were measured, histological sections were prepared and liver lipidome analysis using UPLC-MS coupled with multivariate statistical analysis. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were used to analyze the genes and proteins associated with lipid lowering in HGyp. RESULTS HGyp reduced body weight, serum total cholesterol (TC), triglyceride (TG) and low-density lipoprotein (LDL) and hepatic lipid accumulation in hyperlipidemic obese mice. To explore specific changes in lipid metabolism in relation to HGyp administration, lipid analysis of the liver was performed. Orthogonal partial least squares discriminant analysis (OPLS-DA) score plots showed that HGyp altered lipid metabolism in HFD mice. In particular, fatty acids (FA), triglycerides (DG), TG and ceramides (CER) were significantly altered. Eleven lipids were identified as potential lipid biomarkers, namely TG (18:2/20:5/18:2), TG (18:2/18:3/20:4), DG (18:3/20:0/0:0), Cer (d18:1/19:0), Cer (d16:1/23:0), Ceramide (d18:1/9Z-18:1), PS (19:0/18:3), PS (20:2/0:0), LysoPC (22:5), LysoPE (0:0/18:0), PE (24:0/16:1). Western blot and qRT-PCR analysis showed that these metabolic improvements played a role by down-regulating genes and proteins related to fat production (SREBP1, ACC1, SCD1), up-regulating genes and proteins related to lipid oxidation (CPTA1, PPARα) and lipid transport decomposition in the bile acid pathway (LXRα, PPARγ, FXR, BSEP). CONCLUSION The lipid-lowering effect of gypenosides from heat-processed G. pentaphyllum is regulate lipid homeostasis and metabolism.
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Affiliation(s)
- Peng Xie
- School of Pharmacy, Minzu University of China, Beijing 100081, China
| | - Jin-Bo Xie
- School of Pharmacy, Minzu University of China, Beijing 100081, China
| | - Man-Yu Xiao
- School of Pharmacy, Minzu University of China, Beijing 100081, China
| | - Mei Guo
- School of Pharmacy, Minzu University of China, Beijing 100081, China
| | - Yan-Shuang Qi
- School of Pharmacy, Minzu University of China, Beijing 100081, China
| | - Fang-Fang Li
- School of Pharmacy, Minzu University of China, Beijing 100081, China
| | - Xiang-Lan Piao
- School of Pharmacy, Minzu University of China, Beijing 100081, China.
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Wen Y, Li S, Bao G, Wang J, Liu X, Hu J, Zhao F, Zhao Z, Shi B, Luo Y. Comparative Transcriptome Analysis Reveals the Mechanism Associated With Dynamic Changes in Meat Quality of the Longissimus Thoracis Muscle in Tibetan Sheep at Different Growth Stages. Front Vet Sci 2022; 9:926725. [PMID: 35873690 PMCID: PMC9298548 DOI: 10.3389/fvets.2022.926725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Accepted: 06/06/2022] [Indexed: 11/25/2022] Open
Abstract
Tibetan sheep are mainly distributed in the Qinghai–Tibet Plateau. Its meat is not only essential for the local people but also preferred by the non-inhabitant of this plateau also. To investigate the salient development features and molecular mechanism of the meat difference of LT muscle caused by different growth stages in Tibetan sheep, the carcass performance, meat quality, and comparative transcriptome analysis were performed for investigating the potential molecular mechanism of the meat quality difference of the LT muscle caused by four growth stages [4-months old (4 months), 1.5-years old (1.5 years), 3.5-years old (3.5 years), and 6-years old (6 years)] in the Tibetan sheep. The shear force increased with the increase of age (p < 0.05) while the intramuscular fat (IMF) was the highest at 1.5 y. The AMPK signaling pathway was significantly enriched in the four comparative groups. The weighted gene co-expression network analysis (WGCNA) results showed that the hub genes P4HA2, FBXL4, and PPARA were identified to regulate the meat quality. In summary, 1.5 years was found to be the most suitable slaughter age of the Tibetan sheep which ensured better meat tenderness and higher IMF content. Moreover, the genes LIPE, LEP, ADIPOQ, SCD, and FASN may regulate the transformation of the muscle fiber types through the AMPK signaling pathway, further affecting the meat quality.
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Affiliation(s)
- Yuliang Wen
- Gansu Key Laboratory of Herbivorous Animal Biotechnology, Faculty of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China
| | - Shaobin Li
- Gansu Key Laboratory of Herbivorous Animal Biotechnology, Faculty of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China
| | - Gaoliang Bao
- Gansu Key Laboratory of Herbivorous Animal Biotechnology, Faculty of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China
| | - Jiqing Wang
- Gansu Key Laboratory of Herbivorous Animal Biotechnology, Faculty of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China
| | - Xiu Liu
- Gansu Key Laboratory of Herbivorous Animal Biotechnology, Faculty of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China
| | - Jiang Hu
- Gansu Key Laboratory of Herbivorous Animal Biotechnology, Faculty of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China
| | - Fangfang Zhao
- Gansu Key Laboratory of Herbivorous Animal Biotechnology, Faculty of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China
| | - Zhidong Zhao
- Gansu Key Laboratory of Herbivorous Animal Biotechnology, Faculty of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China
| | - Bingang Shi
- Gansu Key Laboratory of Herbivorous Animal Biotechnology, Faculty of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China
| | - Yuzhu Luo
- Gansu Key Laboratory of Herbivorous Animal Biotechnology, Faculty of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China
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Yanai H, Katsuyama H, Hakoshima M. Effects of a Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator, Pemafibrate, on Metabolic Parameters: A Retrospective Longitudinal Study. Biomedicines 2022; 10:biomedicines10020401. [PMID: 35203610 PMCID: PMC8962310 DOI: 10.3390/biomedicines10020401] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/27/2022] [Accepted: 02/05/2022] [Indexed: 12/07/2022] Open
Abstract
The modulation of peroxisome proliferator-activated receptors (PPARs), the superfamily of steroid–thyroid–retinoid nuclear receptors, is expected to induce an amazing crosstalk between energy-demanding organs. Here, we aimed to study the effects of the novel selective PPARα modulator, pemafibrate, on metabolic parameters in patients with dyslipidemia. We retrospectively studied patients who had taken pemafibrate and compared metabolic parameters at baseline with the data at 3, 6 and 12 months after the start of pemafibrate. Serum triglyceride significantly decreased and high-density lipoprotein-cholesterol significantly increased at 3, 6 and 12 months after the start of pemafibrate. Serum aspartate aminotransferase levels significantly decreased at 3 and 6 after the start of pemafibrate as compared with baseline. Serum alanine aminotransferase and gamma-glutamyl transferase significantly decreased and albumin significantly increased after 3, 6 and 12 months. HbA1c levels significantly decreased after 3 months. Further, serum uric acid significantly decreased after 12 months. Such metabolic favorable changes due to pemafibrate were significantly correlated with changes in serum lipids. In conclusion, we observed a significant improvement of liver function, HbA1c and serum uric acid along with an amelioration of dyslipidemia after the start of pemafibrate.
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Iacob SA, Iacob DG. Non-Alcoholic Fatty Liver Disease in HIV/HBV Patients - a Metabolic Imbalance Aggravated by Antiretroviral Therapy and Perpetuated by the Hepatokine/Adipokine Axis Breakdown. Front Endocrinol (Lausanne) 2022; 13:814209. [PMID: 35355551 PMCID: PMC8959898 DOI: 10.3389/fendo.2022.814209] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 01/10/2022] [Indexed: 12/11/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is strongly associated with the metabolic syndrome and is one of the most prevalent comorbidities in HIV and HBV infected patients. HIV plays an early and direct role in the development of metabolic syndrome by disrupting the mechanism of adipogenesis and synthesis of adipokines. Adipokines, molecules that regulate the lipid metabolism, also contribute to the progression of NAFLD either directly or via hepatic organokines (hepatokines). Most hepatokines play a direct role in lipid homeostasis and liver inflammation but their role in the evolution of NAFLD is not well defined. The role of HBV in the pathogenesis of NAFLD is controversial. HBV has been previously associated with a decreased level of triglycerides and with a protective role against the development of steatosis and metabolic syndrome. At the same time HBV displays a high fibrogenetic and oncogenetic potential. In the HIV/HBV co-infection, the metabolic changes are initiated by mitochondrial dysfunction as well as by the fatty overload of the liver, two interconnected mechanisms. The evolution of NAFLD is further perpetuated by the inflammatory response to these viral agents and by the variable toxicity of the antiretroviral therapy. The current article discusses the pathogenic changes and the contribution of the hepatokine/adipokine axis in the development of NAFLD as well as the implications of HIV and HBV infection in the breakdown of the hepatokine/adipokine axis and NAFLD progression.
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Affiliation(s)
- Simona Alexandra Iacob
- Department of Infectious Diseases, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
- Department of Infectious Diseases, National Institute of Infectious Diseases “Prof. Dr. Matei Bals”, Bucharest, Romania
| | - Diana Gabriela Iacob
- Department of Infectious Diseases, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
- Department of Infectious Diseases, Emergency University Hospital, Bucharest, Romania
- *Correspondence: Diana Gabriela Iacob,
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11
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TGF-β1 signaling can worsen NAFLD with liver fibrosis backdrop. Exp Mol Pathol 2021; 124:104733. [PMID: 34914973 DOI: 10.1016/j.yexmp.2021.104733] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Revised: 11/08/2021] [Accepted: 12/08/2021] [Indexed: 12/11/2022]
Abstract
Non-Alcoholic Fatty Liver Disease (NAFLD) is characterized by the accumulation of fats in the liver. Relatively benign NAFLD often progresses to fibrosis, cirrhosis, and liver malignancies. Although NAFLD precedes fibrosis, continuous lipid overload keeps fueling fibrosis and the process of disease progression remains unhindered. It is well known that TGF-β1 plays its part in liver fibrosis, yet its effects on liver lipid overload remain unknown. As TGF-β1 signaling has been increasingly attempted to manage liver fibrosis, its actions on the primary suspect (NAFLD) are easily ignored. The complex interaction of inflammatory stress and lipid accumulation aided by mediators scuh as pro-inflammatory interleukins and TGF-β1 forms the basis of NAFLD progression. Anticipatorily, the inhibition of TGF-β1 signaling during anti-fibrotic treatment should reverse the NAFLD though the data remain scattered on this subject to date. TGF-β1 signaling pathway is an important drug target in liver fibrosis and abundant literature is available on it, but its direct effects on NAFLD are rarely studied. This review aims to cover the pathogenesis of NAFLD focusing on the role of the TGF-β1 in the disease progression, especially in the backdrop of liver fibrosis.
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12
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Zarghamravanbakhsh P, Frenkel M, Poretsky L. Metabolic causes and consequences of nonalcoholic fatty liver disease (NAFLD). Metabol Open 2021; 12:100149. [PMID: 34870138 PMCID: PMC8626571 DOI: 10.1016/j.metop.2021.100149] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 11/10/2021] [Accepted: 11/10/2021] [Indexed: 12/11/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a multifactorial metabolic disorder that was first described in 1980. It has been prevalent and on the rise for many years and is associated with other metabolic disorders such as obesity and type 2 diabetes mellitus (T2DM). NAFLD can be best described as a metabolic dysfunction that stems from insulin resistance-induced hepatic lipogenesis. This lipogenesis increases oxidative stress and hepatic inflammation and is often potentiated by genetic and gut microbiome dysfunction. As NAFLD progresses from simple steatosis to non-alcoholic steatohepatitis (NASH) and to cirrhosis and hepatocellular carcinoma (HCC), the odds of complications including cardiovascular disease (CVD), chronic kidney disease (CKD), and overall mortality increase. The aim of this review is to describe the metabolic causes and consequences of NAFLD while examining the risks that each stage of NAFLD poses. In this review, the etiology of "lean" NAFLD, the impact of obesity, T2DM, genetics, and microbiome dysbiosis on NAFLD progression are all explored. This review will also discuss the core issue behind the progression of NAFLD: insulin resistance (IR). Upon describing the causes and consequences of NAFLD, the effectiveness of diet modification, lifestyle changes, and glucagon-like peptide 1 receptor (GLP-1) agonists to retard NAFLD progression and stem the rate of complications is examined.
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Affiliation(s)
- Paria Zarghamravanbakhsh
- Division of Endocrinology, Department of Medicine, Lenox Hill Hospital, Northwell Health, 110 East 59th St #8B, New York, NY, 10022, USA
| | - Michael Frenkel
- The Gerald J. Friedman Diabetes Institute, Northwell Health, 110 East 59th St #8B, New York, NY, 10022, USA
| | - Leonid Poretsky
- Division of Endocrinology, Department of Medicine, Lenox Hill Hospital, Northwell Health, 110 East 59th St #8B, New York, NY, 10022, USA
- The Gerald J. Friedman Diabetes Institute, Northwell Health, 110 East 59th St #8B, New York, NY, 10022, USA
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13
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Thapa K, Grewal AS, Kanojia N, Rani L, Sharma N, Singh S. Alcoholic and Non-Alcoholic Liver Diseases: Promising Molecular Drug Targets and their Clinical Development. Curr Drug Discov Technol 2021; 18:333-353. [PMID: 31965945 DOI: 10.2174/1570163817666200121143959] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 11/25/2019] [Accepted: 12/04/2019] [Indexed: 11/22/2022]
Abstract
Alcoholic and non-alcoholic fatty liver diseases have become a serious concern worldwide. Both these liver diseases have an identical pathology, starting from simple steatosis to cirrhosis and, ultimately to hepatocellular carcinoma. Treatment options for alcoholic liver disease (ALD) are still the same as they were 50 years ago which include corticosteroids, pentoxifylline, antioxidants, nutritional support and abstinence; and for non-alcoholic fatty liver disease (NAFLD), weight loss, insulin sensitizers, lipid-lowering agents and anti-oxidants are the only treatment options. Despite broad research in understanding the disease pathophysiology, limited treatments are available for clinical use. Some therapeutic strategies based on targeting a specific molecule have been developed to lessen the consequences of disease and are under clinical investigation. Therefore, focus on multiple molecular targets will help develop an efficient therapeutic strategy. This review comprises a brief overview of the pathogenesis of ALD and NAFLD; recent molecular drug targets explored for ALD and NAFLD that may prove to be effective for multiple therapeutic regimens and also the clinical status of these promising drug targets for liver diseases.
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Affiliation(s)
- Komal Thapa
- Chitkara University School of Basic Sciences, Chitkara University, Himachal Pradesh, India
| | - Ajmer Singh Grewal
- Chitkara University School of Basic Sciences, Chitkara University, Himachal Pradesh, India
| | - Neha Kanojia
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Lata Rani
- Chitkara University School of Basic Sciences, Chitkara University, Himachal Pradesh, India
| | - Neelam Sharma
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Sukhbir Singh
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
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14
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Lu KY, Lin SZ, Primus Dass KT, Lin WJ, Liu SP, Harn HJ. 3-N-butylphthalide protects against high-fat-diet-induced obesity in C57BL/6 mice and increases metabolism in lipid-accumulating cells. Biomed Pharmacother 2021; 139:111687. [PMID: 34243611 DOI: 10.1016/j.biopha.2021.111687] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 04/27/2021] [Accepted: 04/29/2021] [Indexed: 12/25/2022] Open
Abstract
Obesity is one of the world's largest health problems, and 3-N-butylphthalide (NBP), a bioactive compound in celery, has been used in dieting and weight management programs. In this study, NBP prevented high-fat-diet-induced weight gain, reduced the food efficiency ratio, altered the blood biochemical profile, and reduced the obesity-related index. NBP reduced adiposity, white fat depots, liver weight, and hepatic steatosis in obese mice. NBP ameliorated the diabetic state by decreasing glucose levels and improving glucose and insulin tolerance. NBP increased uncoupling protein-1 expression in white adipose tissue and upregulated thermogenesis by enhancing mitochondrial respiration. NBP inhibited white adipocyte development by prohibiting lipid accumulation in human adipose-derived stem cells. NBP increased free fatty acid uptake and the oxygen consumption rate in beige adipocytes. Our results suggest that NBP could be used as functional natural supplement against obesity and its associated disorders.
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Affiliation(s)
- Kang-Yun Lu
- Buddhist Tzu Chi Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan; Graduate Institute of Basic Medical Science, China Medical University, Taichung 404, Taiwan.
| | - Shinn-Zong Lin
- Buddhist Tzu Chi Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan; Department of Neurosurgery, Hualien Tzu Chi Hospital, Hualien 970, Taiwan.
| | | | - Wei-Ju Lin
- Buddhist Tzu Chi Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan
| | - Shih-Ping Liu
- Ph. D. Program for Aging, College of Medicine, China Medical University, Taichung 404, Taiwan; Center for Translational Medicine, China Medical University Hospital, Taichung 404, Taiwan; Department of Social Work, Asia University, Taichung 404, Taiwan.
| | - Horng-Jyh Harn
- Buddhist Tzu Chi Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan; Department of Pathology, Hualien Tzu Chi Hospital and Tzu Chi University, Hualien 970, Taiwan.
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15
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Peng W, Cheng S, Bao Z, Wang Y, Zhou W, Wang J, Yang Q, Chen C, Wang W. Advances in the research of nanodrug delivery system for targeted treatment of liver fibrosis. Biomed Pharmacother 2021; 137:111342. [DOI: 10.1016/j.biopha.2021.111342] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 01/23/2021] [Accepted: 01/27/2021] [Indexed: 02/08/2023] Open
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16
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Micu ES, Amzolini AM, Barău Abu-Alhija A, Forţofoiu MC, Vladu IM, Clenciu D, Mitrea A, Mogoantă SŞ, Crişan AE, Predescu OI, Radu M. Systemic and adipose tissue inflammation in NASH: correlations with histopathological aspects. ROMANIAN JOURNAL OF MORPHOLOGY AND EMBRYOLOGY = REVUE ROUMAINE DE MORPHOLOGIE ET EMBRYOLOGIE 2021; 62:509-515. [PMID: 35024739 PMCID: PMC8848222 DOI: 10.47162/rjme.62.2.17] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Accepted: 12/31/2021] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Non-alcoholic steatohepatitis (NASH) is a progressive form of liver steatosis that involves a risk of progression towards fibrosis, cirrhosis, and end-stage liver disease. Low-grade inflammation is recognized to be involved in non-alcoholic fatty liver disease (NAFLD) pathogeny. Additionally, adipose tissue dysfunction plays an important role in the development of metabolic diseases. PATIENTS, MATERIALS AND METHODS We conducted a study on 68 patients with liver steatosis confirmed through liver biopsy during the surgery. In all the patients, we recorded anthropometric parameters and we performed blood tests for systemic inflammation [high-sensitivity C-reactive protein (hs-CRP), fibrinogen] and serum adipokines related to adipose tissue inflammation (leptin, adiponectin). Additional to histopathological examination, we also performed the immunohistochemical study of inflammatory mononuclear cells. RESULTS The 68 patients had a mean age of 56.57±4.94 years old, had a mean value of hs-CRP of 2.30±0.91 mg∕L, a mean value of leptin of 14.02±17.02 ng∕mL and a mean value of adiponectin of 7.54±0.38 mg∕L. In all the cases studied by liver biopsy, the steatosis exceeded 5% of hepatocytes, but the frequency of NASH was 26.47%. Cluster of differentiation (CD)45-positive, CD4-positive, and CD8-positive T-lymphocytes predominated in the studied cases. We obtained a statistically significant high association between definite NASH and the values of hs-CRP, serum adiponectin and leptin∕adiponectin ratio (p<0.0001). CONCLUSIONS Systemic and adipose tissue inflammation was statistically significant associated with histological lesions of steatosis and NASH, suggesting that the determination of hs-CRP and serum adipokines in dynamics in patients with NAFLD is predictive for the progression of the disease.
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Affiliation(s)
- Elena Simona Micu
- Department of Internal Medicine, Medical Semiology, University of Medicine and Pharmacy of Craiova, Romania
| | - Anca Maria Amzolini
- Department of Internal Medicine, Medical Semiology, University of Medicine and Pharmacy of Craiova, Romania
| | - Anca Barău Abu-Alhija
- Department of Internal Medicine, Medical Semiology, University of Medicine and Pharmacy of Craiova, Romania
| | - Mircea Cătălin Forţofoiu
- Department of Internal Medicine, Medical Semiology, University of Medicine and Pharmacy of Craiova, Romania
| | - Ionela Mihaela Vladu
- Department of Diabetes, Nutrition and Metabolic Diseases, University of Medicine and Pharmacy of Craiova, Romania
| | - Diana Clenciu
- Department of Diabetes, Nutrition and Metabolic Diseases, University of Medicine and Pharmacy of Craiova, Romania
| | - Adina Mitrea
- Department of Diabetes, Nutrition and Metabolic Diseases, University of Medicine and Pharmacy of Craiova, Romania
| | | | - Anda Elena Crişan
- Department of Oncology, University of Medicine and Pharmacy of Craiova, Romania
| | - Octavian Ion Predescu
- Department of Nursing, Faculty of Nursing, Târgu Jiu Subsidiary, Titu Maiorescu University, Bucharest, Romania
| | - Mirela Radu
- Department of Family Medicine, University of Medicine and Pharmacy of Craiova, Romania
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Liu YL, Zhang QZ, Wang YR, Fu LN, Han JS, Zhang J, Wang BM. Astragaloside IV Improves High-Fat Diet-Induced Hepatic Steatosis in Nonalcoholic Fatty Liver Disease Rats by Regulating Inflammatory Factors Level via TLR4/NF-κB Signaling Pathway. Front Pharmacol 2021; 11:605064. [PMID: 33708118 PMCID: PMC7941269 DOI: 10.3389/fphar.2020.605064] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 12/22/2020] [Indexed: 01/18/2023] Open
Abstract
Objective: Astragaloside IV (AS-IV) is the primary bioactive component purified from Astragalus membranaceus which is one of the traditional Chinese medicines. Research studies found that AS-IV has significant pharmacological effects on focal cerebral ischemia/reperfusion, cardiovascular disease, pulmonary disease, liver cirrhosis, and diabetic nephropathy, but little is known about the effects of AS-IV on nonalcoholic fatty liver disease (NAFLD). In this study, we investigated whether AS-IV has beneficial effects on NAFLD in rats and its potential mechanisms. Methods: Male SD rats were fed with high-fat diet (HFD) for 12 weeks to establish NAFLD rat model, and then, the rats were divided into five groups. The control group rats were fed with normal diet for 12 weeks and then were given normal saline (1.0 ml kg−1 day−1) by intragastric administration for 4 weeks. The model group rats were fed with HFD for 12 weeks and then were given normal saline (1.0 ml kg−1 day−1) by intragastric administration for 4 weeks. The AS-IV-L, AS-IV-M, and AS-IV-H groups were treated with 20, 40, and 80 mg kg−1 day−1 of AS-IV by intragastric administration for 4 weeks and given HFD diet. Then, we detected serum transaminase (ALT, AST), blood lipid (TG, TC), inflammatory cytokines (IL-6, IL-8 and TNF-α), liver histology(NAFLD activity score), TLR4/MyD88 signaling pathway in liver tissue. Results: We found AS-IV significantly reduced serum levels of AST, ALT, TG, TNF-α, IL-6, and IL-8 in NAFLD rats and downregulate the expression of TLR4 mRNA, MyD88 mRNA, NF-κB mRNA, and proteins in liver tissue. Moreover, AS-IV could significantly reduce the NAFLD activity score of NAFLD rat liver. Conclusion: In this study, we demonstrated that AS-IV have a protective effect on NAFLD by inhibiting TNF-α, IL-6 and IL-8 levels and down-regulating TLR4, MyD88 and NF-κB expression in rat liver tissues.
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Affiliation(s)
- Ying-Li Liu
- Gastroenterology, the Fourth Central Clinical College, Tianjin Medical University, Tianjin, China.,Gastroenterology, Tianjin Fourth Central Hospital, Tianjin, China
| | - Qiu-Zan Zhang
- Gastroenterology, the Fourth Central Clinical College, Tianjin Medical University, Tianjin, China.,Gastroenterology, Tianjin Fourth Central Hospital, Tianjin, China
| | - Yan-Rong Wang
- Gastroenterology, the Fourth Central Clinical College, Tianjin Medical University, Tianjin, China.,Gastroenterology, Tianjin Fourth Central Hospital, Tianjin, China
| | - Li-Na Fu
- Gastroenterology, the Fourth Central Clinical College, Tianjin Medical University, Tianjin, China.,Gastroenterology, Tianjin Fourth Central Hospital, Tianjin, China
| | - Jing-Shu Han
- Gastroenterology, the Fourth Central Clinical College, Tianjin Medical University, Tianjin, China.,Gastroenterology, Tianjin Fourth Central Hospital, Tianjin, China
| | - Jing Zhang
- Gastroenterology, the Fourth Central Clinical College, Tianjin Medical University, Tianjin, China.,Gastroenterology, Tianjin Fourth Central Hospital, Tianjin, China
| | - Bang-Mao Wang
- Gastroenterology, Tianjin Medical University General Hospital, Tianjin, China
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Wang Y, You Y, Tian Y, Sun H, Li X, Wang X, Wang Y, Liu J. Pediococcus pentosaceus PP04 Ameliorates High-Fat Diet-Induced Hyperlipidemia by Regulating Lipid Metabolism in C57BL/6N Mice. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2020; 68:15154-15163. [PMID: 33300795 DOI: 10.1021/acs.jafc.0c05060] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
In this study, Pediococcus pentococcus PP04 isolated from the Northeast pickled cabbage had good gastrointestinal tolerance and can colonize in the intestine stably. C57BL/6N mice were fed a high-fat diet to build animal models and treated with Pediococcus pentosaceus PP04 to evaluate the antihyperlipidemia effect. After 8 weeks, the indicators of hyperlipidemia, liver injury, and inflammation were measured. The treatment of P. pentosaceus PP04 reduced the gain of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), free fatty acids (FFAs), leptin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), lipopolysaccharides (LPS), and tumor necrosis factor-α (TNF-α) significantly. The western blotting results suggested P. pentosaceus PP04 ameliorated high-fat diet-induced hyperlipidemia by the AMPK signaling pathway, which stimulated lipolysis via upregulation of PPARα and inhibited lipogenesis by downregulation of SREBP-1c, fatty acid synthase (FAS), and stearoyl-CoA desaturase-1 (SCD1) mainly. Furthermore, P. pentosaceus PP04 improved high-fat diet-induced oxidative stress effectively by triggering the Nrf2/CYP2E1 signaling pathway that enhanced the antioxidant activity including superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px).
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Affiliation(s)
- Yu Wang
- College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, China
- Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun 130118, China
| | - Ying You
- College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, China
- Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun 130118, China
| | - Yuan Tian
- College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, China
- Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun 130118, China
| | - Haiyue Sun
- College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, China
- Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun 130118, China
| | - Xia Li
- College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, China
- Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun 130118, China
| | - Xiujuan Wang
- College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, China
- Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun 130118, China
| | - Yuhua Wang
- College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, China
- Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun 130118, China
- National Processing Laboratory for Soybean Industry and Technology, Changchun 130118, China
- National Engineering Laboratory for Wheat and Corn Deep Processing, Changchun 130118, China
| | - Jingsheng Liu
- College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, China
- National Engineering Laboratory for Wheat and Corn Deep Processing, Changchun 130118, China
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Chang ML, Yang Z, Yang SS. Roles of Adipokines in Digestive Diseases: Markers of Inflammation, Metabolic Alteration and Disease Progression. Int J Mol Sci 2020; 21:E8308. [PMID: 33167521 PMCID: PMC7663948 DOI: 10.3390/ijms21218308] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 10/30/2020] [Accepted: 11/01/2020] [Indexed: 12/13/2022] Open
Abstract
Adipose tissue is a highly dynamic endocrine tissue and constitutes a central node in the interorgan crosstalk network through adipokines, which cause pleiotropic effects, including the modulation of angiogenesis, metabolism, and inflammation. Specifically, digestive cancers grow anatomically near adipose tissue. During their interaction with cancer cells, adipocytes are reprogrammed into cancer-associated adipocytes and secrete adipokines to affect tumor cells. Moreover, the liver is the central metabolic hub. Adipose tissue and the liver cooperatively regulate whole-body energy homeostasis via adipokines. Obesity, the excessive accumulation of adipose tissue due to hyperplasia and hypertrophy, is currently considered a global epidemic and is related to low-grade systemic inflammation characterized by altered adipokine regulation. Obesity-related digestive diseases, including gastroesophageal reflux disease, Barrett's esophagus, esophageal cancer, colon polyps and cancer, non-alcoholic fatty liver disease, viral hepatitis-related diseases, cholelithiasis, gallbladder cancer, cholangiocarcinoma, pancreatic cancer, and diabetes, might cause specific alterations in adipokine profiles. These patterns and associated bases potentially contribute to the identification of prognostic biomarkers and therapeutic approaches for the associated digestive diseases. This review highlights important findings about altered adipokine profiles relevant to digestive diseases, including hepatic, pancreatic, gastrointestinal, and biliary tract diseases, with a perspective on clinical implications and mechanistic explorations.
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Affiliation(s)
- Ming-Ling Chang
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 33305, Taiwan
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - Zinger Yang
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA;
| | - Sien-Sing Yang
- Liver Center, Cathay General Hospital Medical Center, Taipei 10630, Taiwan;
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20
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Thorp A, Stine JG. Exercise as Medicine: The Impact of Exercise Training on Nonalcoholic Fatty Liver Disease. ACTA ACUST UNITED AC 2020; 19:402-411. [PMID: 33767944 DOI: 10.1007/s11901-020-00543-9] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Purpose of review Nonalcoholic fatty liver disease (NAFLD) is a leading cause of global liver disease. Because current pharmacologic treatments are ineffective, lifestyle change centered on exercise remains the most effective NAFLD treatment. The aim of this systematic review is to summarize and evaluate the current evidence supporting the use of exercise training as a medical treatment for adult patients with NAFLD. Recent findings At least 150 minutes each week of moderate intensity exercise of any type can improve NAFLD, both with and without modest weight loss. Exercise training reduces hepatic steatosis and liver inflammation, favorably changes body composition, improves vascular endothelial function, increases cardiorespiratory fitness and can lead to histologic response. To date, exercise-based NAFLD trials are limited by small sample size and significant heterogeneity. Summary While several key questions remain unanswered, exercise training will always be an important part of the medical management of patients with NAFLD.
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Affiliation(s)
- Audrey Thorp
- Department of Medicine, The Pennsylvania State University- Milton S. Hershey Medical Center, Hershey PA, USA
| | - Jonathan G Stine
- Division of Gastroenterology and Hepatology, Department of Medicine, The Pennsylvania State University- Milton S. Hershey Medical Center, Hershey PA, USA
- Department of Public Health Sciences, The Pennsylvania State University- Milton S. Hershey Medical Center, Hershey PA, USA
- Liver Center, The Pennsylvania State University- Milton S. Hershey Medical Center, Hershey PA, USA
- Cancer Institute, The Pennsylvania State University- Milton S. Hershey Medical Center, Hershey PA, USA
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21
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Li YY, Cao CY, Zhou YL, Nie YQ, Cao J, Zhou YJ. The roles and interaction of FXR and PPARs in the pathogenesis of nonalcoholic fatty liver disease. Arab J Gastroenterol 2020; 21:162-168. [DOI: 10.1016/j.ajg.2020.04.018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 04/05/2020] [Accepted: 04/24/2020] [Indexed: 12/23/2022]
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Sharma A, Anand SK, Singh N, Dwivedi UN, Kakkar P. Berbamine induced AMPK activation regulates mTOR/SREBP-1c axis and Nrf2/ARE pathway to allay lipid accumulation and oxidative stress in steatotic HepG2 cells. Eur J Pharmacol 2020; 882:173244. [PMID: 32526241 DOI: 10.1016/j.ejphar.2020.173244] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2019] [Revised: 05/18/2020] [Accepted: 06/03/2020] [Indexed: 01/04/2023]
Abstract
Non-alcoholic fatty liver disease is emanating as a global cataclysm. This study was designed to investigate the antioxidative, anti-inflammatory and fat metabolism-regulating potential of berbamine (BBM), a natural bis-benzylisoquinoline alkaloid. BBM attenuated intracellular lipid accumulation in oleic-acid exposed HepG2 cells (0.5 mM) by inhibiting fatty acid uptake, lipogenesis, and promoting fatty acid β-oxidation by activating AMP-activated kinase (AMPK) and peroxisome proliferator-activated receptor (PPAR)-α. Berbamine (5 μM) induced AMPK activation (P < 0.001) via LKB1 (Ser-428) and elevated AMP:ATP ratio (P < 0.001). AMPK activation negatively regulated mTOR and also constrained the nuclear translocation of SREBP-1c and inhibited the lipogenic proteins, stearoyl-CoA desaturase-1 (SCD-1) and fatty acid synthase (FAS) (P < 0.001). BBM stimulated nuclear translocation of redox-sensitive nuclear factor erythroid-2-related factor-2 (Nrf2) and increased hepatic expression of Nrf2 responsive enzymes, HO-1 and Nqo-1. BBM treatment reduced the oxidative burst and pro-inflammatory responses by significantly enhancing hepatic antioxidant defenses [SOD (P < 0.001), catalase (P < 0.001) and cellular glutathione (P < 0.01)] and diminishing NF-κB regulated pro-inflammatory cytokines (TNF-α, and IL-6) levels respectively. TEM analysis confirmed the disruption of mitochondrial structure and reduction in mitochondrial size (50.97%, P < 0.001) in steatotic HepG2 cells which was significantly prevented by 5 μM BBM treatment (71.84% as compared to control, P < 0.01). Pre-treatment of Compound C (AMPK inhibitor, 25 μM) greatly repressed the anti-steatotic properties exhibited by BBM confirming the involvement of AMPK signaling pathway. In summary, the results manifest that BBM reduces intracellular lipid accumulation via AMPK/mTOR/SREBP-1c axis mediated regulation of lipid metabolism and upsurged nuclear stability of Nrf2 by promoting AMPK/Nrf2 association to ameliorate oxidative stress/proinflammatory response.
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Affiliation(s)
- Ankita Sharma
- Herbal Research Laboratory, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan 31, Post Box No. 80, Mahatma Gandhi Marg, Lucknow, 226001, India; Department of Biochemistry, University of Lucknow, Lucknow, 226007, India
| | - Sumit Kr Anand
- Herbal Research Laboratory, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan 31, Post Box No. 80, Mahatma Gandhi Marg, Lucknow, 226001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Neha Singh
- Herbal Research Laboratory, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan 31, Post Box No. 80, Mahatma Gandhi Marg, Lucknow, 226001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | | | - Poonam Kakkar
- Herbal Research Laboratory, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan 31, Post Box No. 80, Mahatma Gandhi Marg, Lucknow, 226001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
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23
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Pirinen E, Auranen M, Khan NA, Brilhante V, Urho N, Pessia A, Hakkarainen A, Kuula J, Heinonen U, Schmidt MS, Haimilahti K, Piirilä P, Lundbom N, Taskinen MR, Brenner C, Velagapudi V, Pietiläinen KH, Suomalainen A. Niacin Cures Systemic NAD + Deficiency and Improves Muscle Performance in Adult-Onset Mitochondrial Myopathy. Cell Metab 2020; 31:1078-1090.e5. [PMID: 32386566 DOI: 10.1016/j.cmet.2020.04.008] [Citation(s) in RCA: 152] [Impact Index Per Article: 30.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 01/24/2020] [Accepted: 04/03/2020] [Indexed: 12/21/2022]
Abstract
NAD+ is a redox-active metabolite, the depletion of which has been proposed to promote aging and degenerative diseases in rodents. However, whether NAD+ depletion occurs in patients with degenerative disorders and whether NAD+ repletion improves their symptoms has remained open. Here, we report systemic NAD+ deficiency in adult-onset mitochondrial myopathy patients. We administered an increasing dose of NAD+-booster niacin, a vitamin B3 form (to 750-1,000 mg/day; clinicaltrials.govNCT03973203) for patients and their matched controls for 10 or 4 months, respectively. Blood NAD+ increased in all subjects, up to 8-fold, and muscle NAD+ of patients reached the level of their controls. Some patients showed anemia tendency, while muscle strength and mitochondrial biogenesis increased in all subjects. In patients, muscle metabolome shifted toward controls and liver fat decreased even 50%. Our evidence indicates that blood analysis is useful in identifying NAD+ deficiency and points niacin to be an efficient NAD+ booster for treating mitochondrial myopathy.
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Affiliation(s)
- Eija Pirinen
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki 00290, Finland.
| | - Mari Auranen
- Research Program of Stem Cells and Metabolism, Faculty of Medicine, University of Helsinki, Helsinki 00290, Finland; Department of Neurosciences, Helsinki University Hospital, Helsinki, Finland
| | - Nahid A Khan
- Research Program of Stem Cells and Metabolism, Faculty of Medicine, University of Helsinki, Helsinki 00290, Finland
| | - Virginia Brilhante
- Research Program of Stem Cells and Metabolism, Faculty of Medicine, University of Helsinki, Helsinki 00290, Finland
| | - Niina Urho
- Department of Neurosciences, Helsinki University Hospital, Helsinki, Finland
| | - Alberto Pessia
- Metabolomics Unit, Institute for Molecular Medicine Finland (FIMM), Helsinki 00290, Finland
| | - Antti Hakkarainen
- Department of Radiology, Medical Imaging Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Department of Neuroscience and Biomedical Engineering, Aalto University School of Science, Espoo 12200, Finland
| | - Juho Kuula
- Department of Radiology, Medical Imaging Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Ulla Heinonen
- Department of Neurosciences, Helsinki University Hospital, Helsinki, Finland
| | - Mark S Schmidt
- Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Kimmo Haimilahti
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki 00290, Finland
| | - Päivi Piirilä
- Unit of Clinical Physiology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Nina Lundbom
- Department of Radiology, Medical Imaging Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Marja-Riitta Taskinen
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki 00290, Finland
| | - Charles Brenner
- Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Vidya Velagapudi
- Metabolomics Unit, Institute for Molecular Medicine Finland (FIMM), Helsinki 00290, Finland
| | - Kirsi H Pietiläinen
- Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki 00290, Finland; Obesity Centre, Abdominal Centre, Endocrinology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Anu Suomalainen
- Research Program of Stem Cells and Metabolism, Faculty of Medicine, University of Helsinki, Helsinki 00290, Finland; HUSlab, Helsinki University Hospital, Helsinki 00290, Finland; Neuroscience Center, HiLife, University of Helsinki, Helsinki 00290, Finland.
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24
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Zhang C, Jia Y, Liu B, Wang G, Zhang Y. TLR4 knockout upregulates the expression of Mfn2 and PGC-1α in a high-fat diet and ischemia-reperfusion mice model of liver injury. Life Sci 2020; 254:117762. [PMID: 32437795 DOI: 10.1016/j.lfs.2020.117762] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Revised: 05/01/2020] [Accepted: 05/05/2020] [Indexed: 12/30/2022]
Abstract
AIMS Patients with nonalcoholic fatty liver disease (NAFLD) have less tolerance to ischemia-reperfusion injury (IRI) of the liver than those with the healthy liver; hence have a higher incidence of severe complications after surgery. This study aimed to investigate the dynamics of the liver and mitochondrial damage and the impact of TLR4 knockout (TLR4KO) on Mfn2 expression in the composite model of NAFLD and IRI. MAIN METHODS We performed high-fat diet (HFD) feeding and ischemia reperfusion (IR) on wild type (WT) and TLR4 knockout TLR4KO mice. KEY FINDINGS The degree of structural and functional injuries to the liver and mitochondria (NAFLD and IRI) is greater than that caused by a single factor (NAFLD or IRI) or a simple superposition of both. The IL-6 and TNF-α expressions were significantly suppressed (P < .05), while PGC-1α and Mfn2 expressions were up-regulated considerably (P < .05) after TLR4KO. Furthermore, mitochondrial fusion increased, while ATP consumption and ROS production decreased significantly after TLR4KO (P < .05). The degree of reduction of compound injury by TLR4KO is more significant than the reduction degree of single factor injury. Also, TNF-α and IL-6 levels can be used predictive markers for mitochondrial damage and liver tolerance to NAFLD and IRI. SIGNIFICANCE TLR4KO upregulates the expression of Mfn2 and PGC-1α in the composite model of NAFLD and IRI. This pathway may be related to IL-6 and TNF-α. This evidence provides theoretical and experimental basis for the subsequent Toll-like receptor 4 (TLR4) receptor targeted therapy.
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Affiliation(s)
- Chaoyang Zhang
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Yinzhao Jia
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Bo Liu
- State Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou Medical University, Wenzhou, China
| | - Guoliang Wang
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Yong Zhang
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China.
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25
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Choi YR, Shim J, Kim MJ. Genistin: A Novel Potent Anti-Adipogenic and Anti-Lipogenic Agent. Molecules 2020; 25:E2042. [PMID: 32349444 PMCID: PMC7248826 DOI: 10.3390/molecules25092042] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 04/17/2020] [Accepted: 04/23/2020] [Indexed: 12/23/2022] Open
Abstract
Soy isoflavones are popular ingredients with anti-adipogenic and anti-lipogenic properties. The anti-adipogenic and anti-lipogenic properties of genistein are well-known, but those of genistin and glycitein remain unknown, and those of daidzein are characterized by contrasting data. Therefore, the purpose of our study was to investigate the effects of daidzein, glycitein, genistein, and genistin on adipogenesis and lipogenesis in 3T3-L1 cells. Proliferation of 3T3-L1 preadipocytes was unaffected by genistin and glycitein, but it was affected by 50 and 100 µM genistein and 100 µM daidzein for 48 h. Among the four isoflavones, only 50 and 100 µM genistin and genistein markedly suppressed lipid accumulation during adipogenesis in 3T3-L1 cells through a similar signaling pathway in a dose-dependent manner. Genistin and genistein suppress adipocyte-specific proteins and genes, such as peroxisome proliferator-activated receptor γ (PPARγ), CCAAT-enhancer-binding protein α (C/EBPα), and adipocyte binding protein 2 (aP2)/fatty acid-binding protein 4 (FABP4), and lipogenic enzymes such as ATP citrate lyase (ACL), acetyl-CoA carboxylase 1 (ACC1), and fatty acid synthase (FAS). Both isoflavones also activate AMP-activated protein kinase α (AMPKα), an essential factor in adipocyte differentiation, and inhibited sterol regulatory element-binding transcription factor 1c (SREBP-1c). These results indicate that genistin is a potent anti-adipogenic and anti-lipogenic agent.
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Affiliation(s)
- Yae Rim Choi
- Research Division of Food Functionality, Korea Food Research Institute, Wanju 55365, Korea (J.S.)
- Department of Food Science and Engineering, Ewha Womans University, Seoul 03760, Korea
| | - Jaewon Shim
- Research Division of Food Functionality, Korea Food Research Institute, Wanju 55365, Korea (J.S.)
| | - Min Jung Kim
- Research Division of Food Functionality, Korea Food Research Institute, Wanju 55365, Korea (J.S.)
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Lee HS, Lee SJ, Ho JN, Cho HY. Preventive Effect of Fermented Chestnut Inner Shell Extract on Obesity-Induced Hepatic Steatosis. Prev Nutr Food Sci 2020; 25:32-40. [PMID: 32292753 PMCID: PMC7143010 DOI: 10.3746/pnf.2020.25.1.32] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 12/02/2019] [Indexed: 01/04/2023] Open
Abstract
This study aimed to investigate the effects of the gallic acid-enriched fermented chestnut inner shell extract (FCCE) by Saccharomyces cerevisiae on a high fat diet (HFD)-induced obesity and hepatic steatosis in vivo mouse model. Mice feeding FCCE exhibited reduced body weight gain compared to those in the HFD-fed group, and showed lower abdominal fat pad weight including epididymal, retroperitoneal, and mesenteric adipose tissue. Further, FCCE administration decreased adipocyte size by suppressing adipogenic factors such as peroxisome proliferator activated receptor γ and CCAAT/ enhancer-binding protein α, and lipogenic factors such as sterol regulatory element-binding protein-1c, fatty acid synthase, and stearoyl CoA desaturase-1. Moreover, FCCE decreased levels of lipids in serum and liver as well as serum alanine aminotransferase and aspartate aminotransferase levels, markers of liver injury. Histological observations of the liver showed that FCCE significantly attenuated HFD-induced hepatic steatosis. The effect of FCCE on hepatic lipid regulatory factors may be partly associated with adenosine monophosphate-activated protein kinase activation. These results suggest that gallic acid-enriched FCCE has potential to be a promising functional food for prevention of obesity and obesity-related fatty liver disease.
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Affiliation(s)
- Hee-Seop Lee
- Deptartment of Food and Biotechnology, Korea University, Sejong 30019, Korea
| | | | - Jin-Nyoung Ho
- Department of Urology, Seoul National University Bundang Hospital, Gyeonggi 13620, Korea
| | - Hong-Yon Cho
- Deptartment of Food and Biotechnology, Korea University, Sejong 30019, Korea
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27
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Boeckmans J, Natale A, Rombaut M, Buyl K, Rogiers V, De Kock J, Vanhaecke T, Rodrigues RM. Anti-NASH Drug Development Hitches a Lift on PPAR Agonism. Cells 2019; 9:E37. [PMID: 31877771 PMCID: PMC7016963 DOI: 10.3390/cells9010037] [Citation(s) in RCA: 98] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 12/15/2019] [Accepted: 12/17/2019] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) affects one-third of the population worldwide, of which a substantial number of patients suffer from non-alcoholic steatohepatitis (NASH). NASH is a severe condition characterized by steatosis and concomitant liver inflammation and fibrosis, for which no drug is yet available. NAFLD is also generally conceived as the hepatic manifestation of the metabolic syndrome. Consequently, well-established drugs that are indicated for the treatment of type 2 diabetes and hyperlipidemia are thought to exert effects that alleviate the pathological features of NASH. One class of these drugs targets peroxisome proliferator-activated receptors (PPARs), which are nuclear receptors that play a regulatory role in lipid metabolism and inflammation. Therefore, PPARs are now also being investigated as potential anti-NASH druggable targets. In this paper, we review the mechanisms of action and physiological functions of PPARs and discuss the position of the different PPAR agonists in the therapeutic landscape of NASH. We particularly focus on the PPAR agonists currently under evaluation in clinical phase II and III trials. Preclinical strategies and how refinement and optimization may improve PPAR-targeted anti-NASH drug testing are also discussed. Finally, potential caveats related to PPAR agonism in anti-NASH therapy are stipulated.
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28
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Tzifi F, Fretzayas A, Chrousos G, Kanaka-Gantenbein C. Non-alcoholic fatty liver infiltration in children: an underdiagnosed evolving disease. Hormones (Athens) 2019; 18:255-265. [PMID: 31140156 DOI: 10.1007/s42000-019-00107-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Accepted: 03/25/2019] [Indexed: 12/21/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) constitutes the most common liver disease, one that is still underdiagnosed in pediatric populations (as well as in the general population), this due to the progressive increase in childhood obesity observed both in developed and developing countries during the last few decades. The pathophysiology of the disease has not been thoroughly clarified yet. The condition displays common pathways in adults and children; however, there are age-related differences. Unlike adults, children with NAFLD require extensive laboratory analysis, because underlying pathologies other than obesity may contribute to the evolution of the disease. Despite the presence of several serum markers and imaging techniques that contribute to NAFLD diagnosis, liver biopsy remains the gold standard diagnostic procedure. Early intervention and obesity prevention are mandatory, as NAFLD is reversible at an early stage. If left undiagnosed and untreated, NAFLD can progress to steatohepatitis (NASH) and subsequent liver failure, a potentially lethal complication. Of note, there are no treatment options when advanced liver fibrosis occurs. This review summarizes literature data on NAFLD in childhood indicating that this is an evolving disease and a significant component of the metabolic syndrome. Pediatricians should be aware of this entity, screening children at high risk and providing appropriate early management, in collaboration with pediatric subspecialists.
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Affiliation(s)
- Flora Tzifi
- First Department of Pediatrics, Division of Endocrinology, Diabetes and Metabolism, Medical School, National and Kapodistrian University of Athens, "Aghia Sophia" Children's Hospital, Athens, Greece.
- Athens Medical Group, Marousi, Greece.
| | | | - George Chrousos
- First Department of Pediatrics, Division of Endocrinology, Diabetes and Metabolism, Medical School, National and Kapodistrian University of Athens, "Aghia Sophia" Children's Hospital, Athens, Greece
| | - Christina Kanaka-Gantenbein
- First Department of Pediatrics, Division of Endocrinology, Diabetes and Metabolism, Medical School, National and Kapodistrian University of Athens, "Aghia Sophia" Children's Hospital, Athens, Greece
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29
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Rahmanabadi A, Mahboob S, Amirkhizi F, Hosseinpour-Arjmand S, Ebrahimi-Mameghani M. Oral α-lipoic acid supplementation in patients with non-alcoholic fatty liver disease: effects on adipokines and liver histology features. Food Funct 2019; 10:4941-4952. [PMID: 31343010 DOI: 10.1039/c9fo00449a] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Considering the importance of adipokines in the pathophysiology of non-alcoholic fatty liver disease (NAFLD), and due to the possible beneficial effects of α-lipoic acid (α-LA) on these adipose-derived hormones, this study aimed to investigate the effect of α-LA supplementation on adipokines and liver steatosis in obese patients with NAFLD. In a double-blind, placebo-controlled randomized clinical trial with two parallel groups, fifty patients with NAFLD were randomized to receive daily supplementation with either two capsules of α-LA (each capsule containing 600 mg α-LA) or two placebo capsules, daily for 12 weeks. At the baseline, all participants received consultation on how to implement a healthy diet into their daily lives. Anthropometric measures, dietary intakes, liver enzymes and adipokines were assessed at the baseline and after 12 weeks of intervention. A significant reduction was observed in the serum levels of insulin (P = 0.024) and leptin (P = 0.019) in the α-LA group compared to the placebo group, but changes in anthropometric and body composition measures, serum glucose (FSG), resistin, irisin and liver enzymes did not differ between the groups. α-LA supplementation resulted in a statistically significant elevation in the quantitative insulin sensitivity check index (QUICKI) (P = 0.033), serum levels of adiponectin (P = 0.008) and adiponectin-to-leptin ratio (P = 0.007) compared to the placebo. The liver steatosis intensity improved significantly. Nonetheless, no significant differences were observed between the study groups in the liver steatosis intensity, at the end of the study. According to the results, α-LA supplementation for 12 weeks improved insulin resistance, serum levels of insulin, adiponectin and leptin without changing anthropometric measures, serum liver enzymes, resistin and irisin.
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Affiliation(s)
- Alireza Rahmanabadi
- Student Research Committee, Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
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30
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Interplay between early-life malnutrition, epigenetic modulation of the immune function and liver diseases. Nutr Res Rev 2019; 32:128-145. [PMID: 30707092 DOI: 10.1017/s0954422418000239] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Early-life nutrition plays a critical role in fetal growth and development. Food intake absence and excess are the two main types of energy malnutrition that predispose to the appearance of diseases in adulthood, according to the hypothesis of 'developmental origins of health and disease'. Epidemiological data have shown an association between early-life malnutrition and the metabolic syndrome in later life. Evidence has also demonstrated that nutrition during this period of life can affect the development of the immune system through epigenetic mechanisms. Thus, epigenetics has an essential role in the complex interplay between environmental factors and genetics. Altogether, this leads to the inflammatory response that is commonly seen in non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome. In conjunction, DNA methylation, covalent modification of histones and the expression of non-coding RNA are the epigenetic phenomena that affect inflammatory processes in the context of NAFLD. Here, we highlight current understanding of the mechanisms underlying developmental programming of NAFLD linked to epigenetic modulation of the immune system and environmental factors, such as malnutrition.
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31
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Al-Radaideh A, Tayyem R, Al-Fayomi K, Nimer N, Almomani A, Alhajjaj S, Agraib L, Hijjawi N. The association of hepatic fat percentage with selected anthropometric and biochemical parameters at 3-Tesla magnetic resonance imaging. Br J Biomed Sci 2019; 76:70-76. [PMID: 30691359 DOI: 10.1080/09674845.2019.1571555] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND AND AIM This relatively comprehensive and multi-parametric study was conducted to investigate an association between hepatic fat percentage (HFP) values measured using high-field magnetic resonance imaging (MRI), anthropometric and biochemical measurements in healthy adults. METHODS Abdominal MRI, anthropometric and biochemical measurements were determined in 156 healthy subjects. HFP values were derived from the MRI, whilst routine lipids, leptin, resistin, IL6 and adiponectin were measured by routine methods. RESULTS Eighty per cent of the calculated HFP values were in the normal range of hepatic fat accumulation. Significant sex-adjusted correlations were found between HFP and waist circumference (WC) (measured by tape), BMI, leptin, resistin, WC (measured by MRI) and hip circumference (all p<0.001) and triglycerides (p=0.01). A significant inverse correlation was detected between HFP and adiponectin (p<0.001). CONCLUSIONS A multi-parametric approach of MRI, biochemical and anthropometric measurements could be adopted to identify subjects at risk of developing non-alcoholic fatty liver disease.
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Affiliation(s)
- A Al-Radaideh
- a Department of Medical Imaging, Faculty of Applied Health Sciences , Hashemite University , Zarqa , Jordan
| | - R Tayyem
- b Department of Nutrition and Food Technology, Faculty of Agriculture , University of Jordan , Amman , Jordan
| | - K Al-Fayomi
- a Department of Medical Imaging, Faculty of Applied Health Sciences , Hashemite University , Zarqa , Jordan
| | - N Nimer
- c Department of Chemistry , College of Sciences and Health Professions, Cleveland State University , Cleveland , OH , USA
| | - A Almomani
- d Department of Radiology , King Hussien Medical Center, Jordanian Royal Medical Services , Amman , Jordan
| | - S Alhajjaj
- e Department of Nutrition , King Hussien Medical Center, Jordanian Royal Medical Services , Amman , Jordan
| | - L Agraib
- b Department of Nutrition and Food Technology, Faculty of Agriculture , University of Jordan , Amman , Jordan
| | - N Hijjawi
- f Department of Medical Laboratory Sciences, Faculty of Applied Health Sciences , Hashemite University , Zarqa , Jordan
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32
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He JY, Wei XH, Li SJ, Liu Y, Hu HL, Li ZZ, Kuang XH, Wang L, Shi X, Yuan ST, Sun L. Adipocyte-derived IL-6 and leptin promote breast Cancer metastasis via upregulation of Lysyl Hydroxylase-2 expression. Cell Commun Signal 2018; 16:100. [PMID: 30563531 PMCID: PMC6299564 DOI: 10.1186/s12964-018-0309-z] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Accepted: 11/25/2018] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Adipocytes make up the major component of breast tissue, accounting for 90% of stromal tissue. Thus, the crosstalk between adipocytes and breast cancer cells may play a critical role in cancer progression. Adipocyte-breast cancer interactions have been considered important for the promotion of breast cancer metastasis. However, the specific mechanisms underlying these interactions are unclear. In this study, we investigated the mechanisms of adipocyte-mediated breast cancer metastasis. METHODS Breast cancer cells were cocultured with mature adipocytes for migration and 3D matrix invasion assays. Next, lentivirus-mediated loss-of-function experiments were used to explore the function of lysyl hydroxylase (PLOD2) in breast cancer migration and adipocyte-dependent migration of breast cancer cells. The role of PLOD2 in breast cancer metastasis was further confirmed using orthotopic mammary fat pad xenografts in vivo. Clinical samples were used to confirm that PLOD2 expression is increased in tumor tissue and is associated with poor prognosis of breast cancer patients. Cells were treated with cytokines and pharmacological inhibitors in order to verify which adipokines were responsible for activation of PLOD2 expression and which signaling pathways were activated in vitro. RESULTS Gene expression profiling and Western blotting analyses revealed that PLOD2 was upregulated in breast cancer cells following coculture with adipocytes; this process was accompanied by enhanced breast cancer cell migration and invasion. Loss-of-function studies indicated that PLOD2 knockdown suppressed cell migration and disrupted the formation of actin stress fibers in breast cancer cells and abrogated the migration induced by following coculture with adipocytes. Moreover, experiments performed in orthotopic mammary fat pad xenografts showed that PLOD2 knockdown could reduce metastasis to the lung and liver. Further, high PLOD2 expression correlated with poor prognosis of breast cancer patients. Mechanistically, adipocyte-derived interleukin-6 (IL-6) and leptin may facilitate PLOD2 upregulation in breast cancer cells and promote breast cancer metastasis in tail vein metastasis assays. Further investigation revealed that adipocyte-derived IL-6 and leptin promoted PLOD2 expression through activation of the JAK/STAT3 and PI3K/AKT signaling pathways. CONCLUSIONS Our study reveals that adipocyte-derived IL-6 and leptin promote PLOD2 expression by activating the JAK/STAT3 and PI3K/AKT signaling pathways, thus promoting breast cancer metastasis.
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Affiliation(s)
- Jin-Yong He
- Jiangsu Key laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China
| | - Xiao-Hui Wei
- Jiangsu Key laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China
| | - Si-Jing Li
- Jiangsu Key laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China
| | - Yang Liu
- Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, China
| | - Hao-Lin Hu
- Breast Disease Center, Zhong-Da Hospital, Southeast University, Nanjing, China
| | - Zheng-Zheng Li
- Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, China
| | - Xin-Hong Kuang
- Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, China
| | - Lai Wang
- Jiangsu Key laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China
| | - Xin Shi
- Department of General Surgery, Zhong-Da Hospital, Southeast University, Nanjing, China
| | - Sheng-Tao Yuan
- Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, China.
| | - Li Sun
- Jiangsu Key laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China.
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Connolly JJ, Ooka K, Lim JK. Future Pharmacotherapy for Non-alcoholic Steatohepatitis (NASH): Review of Phase 2 and 3 Trials. J Clin Transl Hepatol 2018; 6:264-275. [PMID: 30271738 PMCID: PMC6160309 DOI: 10.14218/jcth.2017.00056] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Revised: 02/16/2018] [Accepted: 04/04/2018] [Indexed: 12/15/2022] Open
Abstract
Non-alcoholic steatohepatitis (NASH) results from inflammation and hepatocyte injury in the setting of hepatic steatosis. Non-alcoholic steatohepatitis increases the risk of progression to liver fibrosis and cirrhosis, and is the most rapidly growing etiology for liver failure and indication for liver transplantation in the USA. Weight loss and lifestyle modification remain the standard first-line treatment, as no USA Food and Drug Administration-approved pharmacotherapy currently exists. The past decade has seen an explosion of interest in drug development targeting pathologic pathways in non-alcoholic steatohepatitis, with numerous phase 2 and 3 trials currently in progress. Here, we concisely review the major targets and mechanisms of action by class, summarize results from completed pivotal phase 2 studies, and provide a detailed outline of key active studies with trial data for drugs in development, including obeticholic acid, elafibranor, cenicriviroc and selonsertib.
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Affiliation(s)
- James J. Connolly
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Kohtaro Ooka
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Joseph K. Lim
- Yale Liver Center, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA
- *Correspondence to: Joseph K. Lim, Yale Liver Center, Section of Digestive Diseases, Yale University School of Medicine, 333 Cedar Street, LMP 1080, New Haven, CT 06520-8019, USA. Tel: +1-203-737-6063, Fax: +1-203-785-7273, E-mail:
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Xu H, Fu Q, Zhou Y, Xue C, Olson P, Lynch EC, Zhang KK, Wu C, Murano P, Zhang L, Xie L. A long-term maternal diet intervention is necessary to avoid the obesogenic effect of maternal high-fat diet in the offspring. J Nutr Biochem 2018; 62:210-220. [PMID: 30316166 DOI: 10.1016/j.jnutbio.2018.09.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Revised: 08/22/2018] [Accepted: 09/17/2018] [Indexed: 12/14/2022]
Abstract
Although a pre-pregnancy dietary intervention is believed to be able to prevent offspring obesity, research evidence is absent. We hypothesize that a long period of pre-pregnancy maternal diet transition from a high-fat (HF) diet to a normal-fat (NF) diet effectively prevents offspring obesity, and this preventive effect is independent of maternal body weight change. In our study, female mice were either continued on an NF diet (NF group) or an HF diet (HF group) until weaning, or switched from an HF to an NF for 1 week (H1N group), 5 weeks (H5N group) or 9 weeks (H9N group) before pregnancy. After weaning, the offspring were given the HF diet for 12 weeks to promote obesity. The mothers, regardless of which group, did not display maternal body weight change and glucose intolerance either before pregnancy or after weaning. Compared to the HF group, the H1N and H5N, but not the H9N, offspring developed glucose intolerance earlier, with more severely imbalanced glucose homeostasis. These offspring also displayed hepatocyte degeneration and significant adipocyte hypertrophy associated with higher expression of lipogenesis genes. The molecular mechanistic study showed blunted insulin signaling, overactivated adipocyte Akt signaling and hepatic AMPK signaling with enhanced lipogenesis genes in the H1N and H5N versus the NF offspring. However, maternal H9N diets normalized glucose and lipid metabolism of the offspring via resensitized insulin signaling and normalized Akt and AMPK signaling. In summary, we showed that a long-term maternal diet intervention effectively released the intergenerational obesogenic effect of maternal HF diet independent of maternal weight management.
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Affiliation(s)
- Huiting Xu
- Department of Biomedical Sciences, University of North Dakota, Grand Forks, ND 58202; Hubei Cancer Hospital, Wuhan, Hubei 430079, China
| | - Qiang Fu
- Department of Biomedical Sciences, University of North Dakota, Grand Forks, ND 58202; Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Yi Zhou
- Department of Nutrition and Food Sciences, Texas A&M University, College Station, TX 77843; Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Chengbin Xue
- Department of Biomedical Sciences, University of North Dakota, Grand Forks, ND 58202; Campus Hospital, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China
| | - Patrick Olson
- Department of Biomedical Sciences, University of North Dakota, Grand Forks, ND 58202
| | - Ernest C Lynch
- Department of Biomedical Sciences, University of North Dakota, Grand Forks, ND 58202
| | - Ke K Zhang
- Department of Pathology, University of North Dakota, Grand Forks, ND 58202; ND-INBRE Bioinfomatic Core, University of North Dakota, Grand Forks, ND 58202
| | - Chaodong Wu
- Department of Nutrition and Food Sciences, Texas A&M University, College Station, TX 77843
| | - Peter Murano
- Department of Nutrition and Food Sciences, Texas A&M University, College Station, TX 77843
| | - Lanjing Zhang
- Department of Pathology, University Medical Center of Princeton, Plainsboro, NJ, USA; Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, USA; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
| | - Linglin Xie
- Department of Biomedical Sciences, University of North Dakota, Grand Forks, ND 58202; Department of Nutrition and Food Sciences, Texas A&M University, College Station, TX 77843.
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Martínez R, Kapravelou G, Donaire A, Lopez-Chaves C, Arrebola F, Galisteo M, Cantarero S, Aranda P, Porres JM, López-Jurado M. Effects of a combined intervention with a lentil protein hydrolysate and a mixed training protocol on the lipid metabolism and hepatic markers of NAFLD in Zucker rats. Food Funct 2018; 9:830-850. [PMID: 29364302 DOI: 10.1039/c7fo01790a] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Metabolic syndrome is a cluster of metabolic alterations characterized by central obesity, dyslipidemia, elevated plasma glucose, insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD). In this study, a combined intervention of a lentil protein hydrolysate and a mixed training protocol was assessed in an animal experimental model of genetic obesity and metabolic syndrome. Thirty-two male obese and 32 lean Zucker rats were divided into eight different experimental groups. Rats performed a mixed exercise protocol or had a sedentary lifestyle and were administered a lentil protein hydrolysate or placebo. Daily food intake, weekly body weight gain, plasma parameters of glucose and lipid metabolisms, body composition, hepatic weight, total fat content and fatty acid profile, as well as gene expression of lipogenic and lipolytic nuclear transcription factors and their target genes were measured. Obese Zucker rats exhibited higher body and liver weight and fat content than did their lean counterparts. Such alterations were related to modifications in aerobic capacity, plasma biochemical parameters of glucose and lipid metabolisms, hepatic fatty acid profile and gene expression of nuclear transcription factors SREBP1c, PPARα, LXR and associated lipogenic and lipolytic enzymes. The interventions tested did not affect body weight gain but improved aerobic capacity, reduced hepatomegalia and steatosis associated with NAFLD and relieved the adverse effects produced by this condition in glucose and lipid metabolisms through the modulation in the expression of different genes involved in diverse metabolic pathways.
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Affiliation(s)
- Rosario Martínez
- Department of Physiology, Institute of Nutrition and Food Technology, Centre for Biomedical Research, Sport and Health Research Centre, University of Granada, Spain.
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Lee HJ, Jung H, Cho H, Lee K, Hwang KT. Black Raspberry Seed Oil Improves Lipid Metabolism by Inhibiting Lipogenesis and Promoting Fatty-Acid Oxidation in High-Fat Diet-Induced Obese Mice and db
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Mice. Lipids 2018; 53:491-504. [DOI: 10.1002/lipd.12050] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Revised: 05/10/2018] [Accepted: 05/18/2018] [Indexed: 12/12/2022]
Affiliation(s)
- Hee Jae Lee
- Department of Food and Nutrition, and Research Institute of Human Ecology; Seoul National University, 1 Gwanak-ro, Gwanak-gu; Seoul, 08826 South Korea
| | - Hana Jung
- Department of Food and Nutrition, and Research Institute of Human Ecology; Seoul National University, 1 Gwanak-ro, Gwanak-gu; Seoul, 08826 South Korea
- Department of Human Ecology; Korea National Open University, 86 Daehak-ro, Jongno-gu; Seoul, 03087 South Korea
| | - Hyunnho Cho
- Department of Food and Nutrition, and Research Institute of Human Ecology; Seoul National University, 1 Gwanak-ro, Gwanak-gu; Seoul, 08826 South Korea
| | - Kiuk Lee
- Department of Food and Nutrition, and Research Institute of Human Ecology; Seoul National University, 1 Gwanak-ro, Gwanak-gu; Seoul, 08826 South Korea
| | - Keum Taek Hwang
- Department of Food and Nutrition, and Research Institute of Human Ecology; Seoul National University, 1 Gwanak-ro, Gwanak-gu; Seoul, 08826 South Korea
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Li YY, Tang D, Du YL, Cao CY, Nie YQ, Cao J, Zhou YJ. Fatty liver mediated by peroxisome proliferator-activated receptor-α DNA methylation can be reversed by a methylation inhibitor and curcumin. J Dig Dis 2018; 19:421-430. [PMID: 29802754 DOI: 10.1111/1751-2980.12610] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Revised: 04/28/2018] [Accepted: 05/23/2018] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Our studies in vitro and in vivo aimed to investigate the influence of DNA methylation of peroxisome proliferator activated receptor-α (PPAR-α) gene in non-alcoholic fatty liver disease (NAFLD) pathogenesis and to observe whether the DNA methylation inhibitor 5-Aza-2'-deoxycytidine (5-Aza-CdR) and the herbal medicine curcumin might reverse the effect both in vivo and in vitro. METHODS Steatotic hepatocyte model of cell lines and NAFLD rat models were established following protocols documented in previous studies. Subsequently, the models received 5-Aza-CdR and curcumin treatment. Morphological, histological and laboratory variables in each group were determined by routine methods, including PPAR-α mRNA expression by polymerase chain reaction (PCR), PPAR-α protein expression by Western blot and DNA methylation by pyrosequencing. RESULTS The steatotic hepatocyte model and NAFLD rat model were completely established. The expressions of PPAR-α mRNA and protein were significantly lower in the steatotic hepatocyte and NAFLD rat model groups than in the controls (P < 0.05). The mean DNA methylation levels of the PPAR-α gene were significantly higher in the two steatotic model groups than in the controls, especially at several CpG sites (P < 0.05). 5-Aza-CdR and curcumin treatment significantly reversed the DNA methylation levels, increased PPAR-α mRNA and protein expression, and improved lipid accumulation in the two steatotic models (P < 0.05). CONCLUSIONS DNA methylation at the PPAR-α gene is involved in the pathogenesis of NAFLD and is possibly reversible by 5-Aza-CdR and curcumin. Curcumin may be a promising candidate for NAFLD therapy.
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Affiliation(s)
- Yu Yuan Li
- Department of Gastroenterology and Hepatology, Guangzhou Digestive Diseases Center, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong Province, China
| | - Dan Tang
- Department of Gastroenterology and Hepatology, Guangzhou Digestive Diseases Center, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong Province, China
| | - Yan Lei Du
- Department of Gastroenterology and Hepatology, Guangzhou Digestive Diseases Center, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong Province, China
| | - Chuang Yu Cao
- Department of Gastroenterology and Hepatology, Guangzhou Digestive Diseases Center, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong Province, China
| | - Yu Qiang Nie
- Department of Gastroenterology and Hepatology, Guangzhou Digestive Diseases Center, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong Province, China
| | - Jie Cao
- Department of Gastroenterology and Hepatology, Guangzhou Digestive Diseases Center, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong Province, China
| | - Yong Jian Zhou
- Department of Gastroenterology and Hepatology, Guangzhou Digestive Diseases Center, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong Province, China
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Morphofunctional Changes After Sleeve Gastrectomy and Very Low Calorie Diet in an Animal Model of Non-Alcoholic Fatty Liver Disease. Obes Surg 2018; 28:142-151. [PMID: 28710554 DOI: 10.1007/s11695-017-2805-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease and is found in 70% of obese people. The evidence available to date suggests that bariatric surgery could be an effective treatment by reducing weight and also by improving metabolic complications in the long term. This work aimed to compare, in a diet-induced NAFLD animal model, the effect of both sleeve gastrectomy (SG) and very-low calorie diet (VLCD). METHODS Thirty-five Wistar rats were divided into control rats (n = 7) and obese rats fed a high-fat diet (HFD). After 10 weeks, the obese rats were subdivided into four groups: HFD (n = 7), VLCD (n = 7), and rats submitted to either a sham operation (n = 7) or SG (n = 7). Both liver tissue and blood samples were processed to evaluate steatosis and NASH changes in histology (Oil Red, Sirius Red and H&E); presence of endothelial damage (CD31, Moesin/p-Moesin, Akt/p-Akt, eNOS/p-eNOS), oxidative stress (iNOS) and fibrosis (αSMA, Col1, PDGF, VEGF) proteins in liver tissue; and inflammatory (IL6, IL10, MCP-1, IL17α, TNFα), liver biochemical function, and hormonal (leptin, ghrelin, visfatin and insulin) alterations in plasma. RESULTS Both VLCD and SG improved histology, but only SG induced a significant weight loss, improved endothelial damage, and a decreased cardiovascular risk by reducing insulin resistance (IR), leptin, total cholesterol, and triglyceride levels. There were no relevant variations in the inflammatory and fibrosis markers. CONCLUSION Our study suggests a slight superiority of SG over VLCD by improving not only the histology but also the IR and cardiovascular risk markers related to NAFLD.
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Kim JS, Lee SG, Min K, Kwon TK, Kim HJ, Nam JO. Eupatilin inhibits adipogenesis through suppression of PPARγ activity in 3T3-L1 cells. Biomed Pharmacother 2018; 103:135-139. [PMID: 29649628 DOI: 10.1016/j.biopha.2018.03.073] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2017] [Revised: 03/12/2018] [Accepted: 03/12/2018] [Indexed: 01/18/2023] Open
Abstract
Eupatilin (5,7-dihydroxy-3',4',6-trimethoxyflavone) is a flavonoid compound from Artemisia species that possesses beneficial biological activities such as anti-cancer, anti-oxidation, and anti-inflammatory activities. However, an anti-adipogenic effect has not yet been reported. In this study, we found that eupatilin significantly inhibited the adipogenesis of 3T3-L1 adipocytes. Eupatilin decreased intracellular lipid accumulation and suppressed the expression level of key adipogenic regulators in 3T3-L1 adipocytes, including peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT-enhancer-binding protein alpha (C/EBPα), in a concentration-dependent manner. These results show that eupatilin significantly inhibits 3T3-L1 cell differentiation and suggest that it has potential as a novel anti-obesity therapy.
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Affiliation(s)
- Jin Soo Kim
- Department of Food Science and Biotechnology, Kyungpook National University, Daegu 41566, South Korea
| | - Seul Gi Lee
- Department of Food Science and Biotechnology, Kyungpook National University, Daegu 41566, South Korea
| | - Kyoungjin Min
- Department of Immunology, School of Medicine, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu 704-701, South Korea
| | - Taeg Kyu Kwon
- Department of Immunology, School of Medicine, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu 704-701, South Korea
| | - Ha-Jeong Kim
- Department of Physiology, Cell and Matrix Research Institute, BK21 Plus KNU Biomedical Convergence Program, Tumor Heterogeneity and Network (THEN) Research Center, Kyungpook National University School of Medicine, Daegu, South Korea
| | - Ju-Ock Nam
- Department of Food Science and Biotechnology, Kyungpook National University, Daegu 41566, South Korea; Institute of Agricultural Science & Technology, Kyungpook National University, Daegu 41566, South Korea.
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Zhao N, Li X, Feng Y, Han J, Feng Z, Li X, Wen Y. The Nuclear Orphan Receptor Nur77 Alleviates Palmitate-induced Fat Accumulation by Down-regulating G0S2 in HepG2 Cells. Sci Rep 2018; 8:4809. [PMID: 29556076 PMCID: PMC5859288 DOI: 10.1038/s41598-018-23141-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Accepted: 03/07/2018] [Indexed: 12/11/2022] Open
Abstract
Excessive triglyceride accumulation in hepatocytes is the hallmark of obesity-associated nonalcoholic fatty liver disease (NAFLD). Elevated levels of the saturated free fatty acid palmitate in obesity are a major contributor to excessive hepatic lipid accumulation. The nuclear orphan receptor Nur77 is a transcriptional regulator and a lipotoxicity sensor. Using human HepG2 hepatoma cells, this study aimed to investigate the functional role of Nur77 in palmitate-induced hepatic steatosis. The results revealed that palmitate significantly induced lipid accumulation and suppressed lipolysis in hepatocytes. In addition, palmitate significantly suppressed Nur77 expression and stimulated the expression of peroxisome proliferator-activated receptor γ (PPARγ) and its target genes. Nur77 overexpression significantly reduced palmitate-induced expression of PPARγ and its target genes. Moreover, Nur77 overexpression attenuated lipid accumulation and augmented lipolysis in palmitate-treated hepatocytes. Importantly, G0S2 knockdown significantly attenuated lipid accumulation and augmented lipolysis in palmitate-treated hepatocytes, whereas G0S2 knockdown had no effect on the palmitate-induced expression of Nur77, PPARγ, or PPARγ target genes. In summary, palmitate suppresses Nur77 expression in HepG2 cells, and Nur77 overexpression alleviates palmitate-induced hepatic fat accumulation by down-regulating G0S2. These results display a novel molecular mechanism linking Nur77-regulated G0S2 expression to palmitate-induced hepatic steatosis.
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Affiliation(s)
- Naiqian Zhao
- Department of Gerontology, Second Hospital of Shanxi Medical University, 382 Wuyi Road, Taiyuan, 030001, Shanxi, China.
| | - Xiaoyan Li
- Department of Infectious Diseases, First People's Hospital of Jinzhong, 85 Shuncheng Street, Jinzhong, 030600, Shanxi, China
| | - Ying Feng
- Department of Gerontology, Second Hospital of Shanxi Medical University, 382 Wuyi Road, Taiyuan, 030001, Shanxi, China
| | - Jinxiang Han
- Department of Gerontology, Second Hospital of Shanxi Medical University, 382 Wuyi Road, Taiyuan, 030001, Shanxi, China
| | - Ziling Feng
- Department of Infectious Diseases, First People's Hospital of Jinzhong, 85 Shuncheng Street, Jinzhong, 030600, Shanxi, China
| | - Xifeng Li
- Department of Infectious Diseases, First People's Hospital of Jinzhong, 85 Shuncheng Street, Jinzhong, 030600, Shanxi, China
| | - Yanfang Wen
- Department of Infectious Diseases, First People's Hospital of Jinzhong, 85 Shuncheng Street, Jinzhong, 030600, Shanxi, China
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Zhao NQ, Li XY, Wang L, Feng ZL, Li XF, Wen YF, Han JX. Palmitate induces fat accumulation by activating C/EBPβ-mediated G0S2 expression in HepG2 cells. World J Gastroenterol 2017; 23:7705-7715. [PMID: 29209111 PMCID: PMC5703930 DOI: 10.3748/wjg.v23.i43.7705] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Revised: 09/27/2017] [Accepted: 09/28/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To determine the role of G0/G1 switch gene 2 (G0S2) and its transcriptional regulation in palmitate-induced hepatic lipid accumulation.
METHODS HepG2 cells were treated with palmitate, or palmitate in combination with CCAAT/enhancer binding protein (C/EBP)β siRNA or G0S2 siRNA. The mRNA expression of C/EBPβ, peroxisome proliferator-activated receptor (PPAR)γ and PPARγ target genes (G0S2, GPR81, GPR109A and Adipoq) was examined by qPCR. The protein expression of C/EBPβ, PPARγ, and G0S2 was determined by Western blotting. Lipid accumulation was detected with Oil Red O staining and quantified by absorbance value of the extracted Oil Red O dye. Lipolysis was evaluated by measuring the amount of glycerol released into the medium.
RESULTS Palmitate caused a dose-dependent increase in lipid accumulation and a dose-dependent decrease in lipolysis in HepG2 cells. In addition, palmitate increased the mRNA expression of C/EBPβ, PPARγ, and PPARγ target genes (G0S2, GPR81, GPR109A, and Adipoq) and the protein expression of C/EBPβ, PPARγ, and G0S2 in a dose-dependent manner. Knockdown of C/EBPβ decreased palmitate-induced PPARγ and its target genes (G0S2, GPR81, GPR109A, and Adipoq) mRNA expression and palmitate-induced PPARγ and G0S2 protein expression in HepG2 cells. Knockdown of C/EBPβ also attenuated lipid accumulation and augmented lipolysis in palmitate-treated HepG2 cells. G0S2 knockdown attenuated lipid accumulation and augmented lipolysis, while G0S2 knockdown had no effects on the mRNA expression of C/EBPβ, PPARγ, and PPARγ target genes (GPR81, GPR109A and Adipoq) in palmitate-treated HepG2 cells.
CONCLUSION Palmitate can induce lipid accumulation in HepG2 cells by activating C/EBPβ-mediated G0S2 expression.
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Affiliation(s)
- Nai-Qian Zhao
- Department of Gerontology, the Second Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Xiao-Yan Li
- Department of Infectious Diseases, the First People’s Hospital of Jinzhong, Jinzhong 030600, Shanxi Province, China
| | - Li Wang
- Department of Gerontology, the Second Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Zi-Ling Feng
- Department of Infectious Diseases, the First People’s Hospital of Jinzhong, Jinzhong 030600, Shanxi Province, China
| | - Xi-Fen Li
- Department of Infectious Diseases, the First People’s Hospital of Jinzhong, Jinzhong 030600, Shanxi Province, China
| | - Yan-Fang Wen
- Department of Infectious Diseases, the First People’s Hospital of Jinzhong, Jinzhong 030600, Shanxi Province, China
| | - Jin-Xiang Han
- Department of Gerontology, the Second Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
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Poilil Surendran S, George Thomas R, Moon MJ, Jeong YY. Nanoparticles for the treatment of liver fibrosis. Int J Nanomedicine 2017; 12:6997-7006. [PMID: 29033567 PMCID: PMC5614791 DOI: 10.2147/ijn.s145951] [Citation(s) in RCA: 92] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Chronic liver diseases represent a global health problem due to their high prevalence worldwide and the limited available curative treatment options. They can result from various causes, both infectious and noninfectious diseases. The application of nanoparticle (NP) systems has emerged as a rapidly evolving area of interest for the safe delivery of various drugs and nucleic acids for chronic liver diseases. This review presents the pathogenesis, diagnosis and the emerging nanoparticulate systems used in the treatment of chronic liver diseases caused by liver fibrosis. Activated hepatic stellate cell (HSC) is considered to be the main mechanism for liver fibrosis. Ultrasonography and magnetic resonance imaging techniques are widely used noninvasive diagnostic methods for hepatic fibrosis. A variety of nanoparticulate systems are mainly focused on targeting HSC in the treatment of hepatic fibrosis. As early liver fibrosis is reversible by current NP therapy, it is being studied in preclinical as well as clinical trials. Among various nanoparticulate systems, inorganic NPs, liposomes and nanomicelles have been widely studied due to their distinct properties to deliver drugs as well as other therapeutic moieties. Liposomal NPs in clinical trials is considered to be a milestone in the treatment of hepatic fibrosis. Currently, NP therapy for liver fibrosis is updating fast, and hopefully, it can be the future remedy for liver fibrosis.
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Affiliation(s)
- Suchithra Poilil Surendran
- Department of Radiology, BioMolecular Theranostics (BiT) Lab, Chonnam National University Medical School, Chonnam National University Hwasun Hospital (CNUHH), South Korea
| | - Reju George Thomas
- Department of Radiology, BioMolecular Theranostics (BiT) Lab, Chonnam National University Medical School, Chonnam National University Hwasun Hospital (CNUHH), South Korea
| | - Myeong Ju Moon
- Department of Radiology, BioMolecular Theranostics (BiT) Lab, Chonnam National University Medical School, Chonnam National University Hwasun Hospital (CNUHH), South Korea
| | - Yong Yeon Jeong
- Department of Radiology, BioMolecular Theranostics (BiT) Lab, Chonnam National University Medical School, Chonnam National University Hwasun Hospital (CNUHH), South Korea
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Engin A. Non-Alcoholic Fatty Liver Disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 960:443-467. [DOI: 10.1007/978-3-319-48382-5_19] [Citation(s) in RCA: 87] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Fermentation with Lactobacillus enhances the preventive effect of garlic extract on high fat diet-induced hepatic steatosis in mice. J Funct Foods 2017. [DOI: 10.1016/j.jff.2016.12.043] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
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Tiburcio TC, Willebrords J, da Silva TC, Alves Pereira IV, Nogueira MS, Crespo Yanguas S, Maes M, dos Anjos Silva E, Zaidan Dagli ML, Alves de Castro I, Pinto Oliveira C, Vinken M, Cogliati B. Connexin32 deficiency is associated with liver injury, inflammation and oxidative stress in experimental non-alcoholic steatohepatitis. Clin Exp Pharmacol Physiol 2017; 44:197-206. [PMID: 27859493 PMCID: PMC5689377 DOI: 10.1111/1440-1681.12701] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2016] [Revised: 11/11/2016] [Accepted: 11/15/2016] [Indexed: 01/09/2023]
Abstract
Non-alcoholic steatohepatitis is a highly prevalent liver pathology featured by hepatocellular fat deposition and inflammation. Connexin32, which is the major building block of hepatocellular gap junctions, has a protective role in hepatocarcinogenesis and is downregulated in chronic liver diseases. However, the role of connexin32 in non-alcoholic steatohepatitis remains unclear. Connexin32-/- mice and their wild-type littermates were fed a choline-deficient high-fat diet. The manifestation of non-alcoholic steatohepatitis was evaluated based on a battery of clinically relevant read-outs, including histopathological examination, diverse indicators of inflammation and liver damage, in-depth lipid analysis, assessment of oxidative stress, insulin and glucose tolerance, liver regeneration and lipid-related biomarkers. Overall, more pronounced liver damage, inflammation and oxidative stress were observed in connexin32-/- mice compared to wild-type animals. No differences were found in insulin and glucose tolerance measurements and liver regeneration. However, two lipid-related genes, srebf1 and fabp3, were upregulated in Cx32-/- mice in comparison with wild-type animals. These findings suggest that connexin32-based signalling is not directly involved in steatosis as such, but rather in the sequelae of this process, which underlie progression of non-alcoholic steatohepatitis.
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Affiliation(s)
- Taynã Cristina Tiburcio
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, Av. Prof. Dr. Orlando Marques de Paiva 87, 05508-270 São Paulo, Brazil
| | - Joost Willebrords
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium
| | - Tereza Cristina da Silva
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, Av. Prof. Dr. Orlando Marques de Paiva 87, 05508-270 São Paulo, Brazil
| | - Isabel Veloso Alves Pereira
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, Av. Prof. Dr. Orlando Marques de Paiva 87, 05508-270 São Paulo, Brazil
| | - Marina Sayuri Nogueira
- Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, Av. Prof. Lineu Prestes 580, São Paulo, Brazil
| | - Sara Crespo Yanguas
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium
| | - Michaël Maes
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium
| | - Elisangela dos Anjos Silva
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, Av. Prof. Dr. Orlando Marques de Paiva 87, 05508-270 São Paulo, Brazil
| | - Maria Lucia Zaidan Dagli
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, Av. Prof. Dr. Orlando Marques de Paiva 87, 05508-270 São Paulo, Brazil
| | - Inar Alves de Castro
- Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, Av. Prof. Lineu Prestes 580, São Paulo, Brazil
| | - Cláudia Pinto Oliveira
- Department of Gastroenterology, Clinical Division, Hepatology Branch, University of São Paulo School of Medicine, Av. Dr. Arnaldo 455, São Paulo, Brazil
| | - Mathieu Vinken
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium
| | - Bruno Cogliati
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, Av. Prof. Dr. Orlando Marques de Paiva 87, 05508-270 São Paulo, Brazil
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de Las Heras N, Valero-Muñoz M, Martín-Fernández B, Ballesteros S, López-Farré A, Ruiz-Roso B, Lahera V. Molecular factors involved in the hypolipidemic- and insulin-sensitizing effects of a ginger (Zingiber officinale Roscoe) extract in rats fed a high-fat diet. Appl Physiol Nutr Metab 2017; 42:209-215. [PMID: 28125276 DOI: 10.1139/apnm-2016-0374] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2023]
Abstract
Hypolipidemic and hypoglycemic properties of ginger in animal models have been reported. However, information related to the mechanisms and factors involved in the metabolic effects of ginger at a hepatic level are limited. The aim of the present study was to investigate molecular factors involved in the hypoglycemic and hypolipidemic effects of a hydroethanolic ginger extract (GE) in the liver of rats fed a high-fat diet (HFD). The study was conducted in male Wistar rats divided into the following 3 groups: (i) Rats fed a standard diet (3.5% fat), the control group; (ii) rats fed an HFD (33.5% fat); and (iii) rats fed an HFD treated with GE (250 mg·kg-1·day-1) for 5 weeks (HFD+GE). Plasma levels of glucose, insulin, lipid profile, leptin, and adiponectin were measured. Liver expression of glycerol phosphate acyltransferase (GPAT), cholesterol 7 alpha-hydroxylase, peroxisome proliferator-activated receptors (PPAR), PPARα and PPARγ, glucose transporter 2 (GLUT-2), liver X receptor, sterol regulatory element-binding protein (SREBP1c), connective tissue growth factor (CTGF), and collagen I was measured. Data were analyzed using a 1-way ANOVA, followed by a Newman-Keuls test if differences were noted. The study showed that GE improved lipid profile and attenuated the increase of plasma levels of glucose, insulin, and leptin in HFD rats. This effect was associated with a higher liver expression of PPARα, PPARγ, and GLUT-2 and an enhancement of plasma adiponectin levels. Furthermore, GE reduced liver expression of GPAT, SREBP1c, CTGF, and collagen I. The results suggest that GE might be considered as an alternative therapeutic strategy in the management of overweight and hepatic and metabolic-related alterations.
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Affiliation(s)
- Natalia de Las Heras
- a Department of Physiology, Complutense University, School of Medicine, Madrid - 28040, Spain
| | - María Valero-Muñoz
- a Department of Physiology, Complutense University, School of Medicine, Madrid - 28040, Spain
| | | | - Sandra Ballesteros
- a Department of Physiology, Complutense University, School of Medicine, Madrid - 28040, Spain
| | - Antonio López-Farré
- b Department of Medicine, Complutense University, School of Medicine, Madrid - 28040, Spain
| | - Baltasar Ruiz-Roso
- c Department of Nutrition, Complutense University, School of Pharmacy, Madrid - 28040, Spain
| | - Vicente Lahera
- a Department of Physiology, Complutense University, School of Medicine, Madrid - 28040, Spain
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PPARs and Mitochondrial Metabolism: From NAFLD to HCC. PPAR Res 2016; 2016:7403230. [PMID: 28115925 PMCID: PMC5223052 DOI: 10.1155/2016/7403230] [Citation(s) in RCA: 297] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Revised: 11/08/2016] [Accepted: 11/10/2016] [Indexed: 11/17/2022] Open
Abstract
Metabolic related diseases, such as type 2 diabetes, metabolic syndrome, and nonalcoholic fatty liver disease (NAFLD), are widespread threats which bring about a significant burden of deaths worldwide, mainly due to cardiovascular events and cancer. The pathogenesis of these diseases is extremely complex, multifactorial, and only partially understood. As the main metabolic organ, the liver is central to maintain whole body energetic homeostasis. At the cellular level, mitochondria are the metabolic hub connecting and integrating all the main biochemical, hormonal, and inflammatory signaling pathways to fulfill the energetic and biosynthetic demand of the cell. In the liver, mitochondria metabolism needs to cope with the energetic regulation of the whole body. The nuclear receptors PPARs orchestrate lipid and glucose metabolism and are involved in a variety of diseases, from metabolic disorders to cancer. In this review, focus is placed on the roles of PPARs in the regulation of liver mitochondrial metabolism in physiology and pathology, from NAFLD to HCC.
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Panera N, Della Corte C, Crudele A, Stronati L, Nobili V, Alisi A. Recent advances in understanding the role of adipocytokines during non-alcoholic fatty liver disease pathogenesis and their link with hepatokines. Expert Rev Gastroenterol Hepatol 2016; 10:393-403. [PMID: 26654761 DOI: 10.1586/17474124.2016.1110485] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is currently considered the main cause of chronic liver disease worldwide. Mechanisms leading to the development and progression of this disease are topics of great interest for researchers and clinicians. The current multi-hit hypothesis has thrown the crosstalk between liver and adipose tissue into sharp focus. It is well known that adipose tissue produces circulating factors, known as adipocytokines, which exert several effects on liver cells, promoting the onset of NAFLD and its progression to non-alcoholic steatohepatitis in obese subjects. In a similar way, hepatocytes may also respond to obesogenic stimuli by producing and releasing hepatokines into the circulation. Here, the authors provide an overview of recent advances in our understanding of the role of the most relevant adipocytokines and hepatokines in NAFLD pathogenesis, highlighting their possible molecular and functional interactions.
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Affiliation(s)
- Nadia Panera
- a Liver Research Unit , 'Bambino Gesù' Children's Hospital, IRCCS , Rome , Italy
| | - Claudia Della Corte
- b Hepato-Metabolic Disease Unit , 'Bambino Gesù' Children's Hospital, IRCCS , Rome , Italy
| | - Annalisa Crudele
- a Liver Research Unit , 'Bambino Gesù' Children's Hospital, IRCCS , Rome , Italy
| | - Laura Stronati
- c Department of Radiobiology and Human Health , ENEA , Rome , Italy
| | - Valerio Nobili
- b Hepato-Metabolic Disease Unit , 'Bambino Gesù' Children's Hospital, IRCCS , Rome , Italy
| | - Anna Alisi
- a Liver Research Unit , 'Bambino Gesù' Children's Hospital, IRCCS , Rome , Italy
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Jurado-Ruiz E, Varela LM, Luque A, Berná G, Cahuana G, Martinez-Force E, Gallego-Durán R, Soria B, de Roos B, Romero Gómez M, Martín F. An extra virgin olive oil rich diet intervention ameliorates the nonalcoholic steatohepatitis induced by a high-fat “Western-type” diet in mice. Mol Nutr Food Res 2016; 61. [DOI: 10.1002/mnfr.201600549] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Revised: 10/07/2016] [Accepted: 10/11/2016] [Indexed: 02/06/2023]
Affiliation(s)
- Enrique Jurado-Ruiz
- Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER); Universidad Pablo Olavide; Seville Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM); Madrid Spain
| | - Lourdes M. Varela
- Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER); Universidad Pablo Olavide; Seville Spain
| | - Amparo Luque
- Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER); Universidad Pablo Olavide; Seville Spain
| | - Genoveva Berná
- Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER); Universidad Pablo Olavide; Seville Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM); Madrid Spain
| | - Gladys Cahuana
- Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER); Universidad Pablo Olavide; Seville Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM); Madrid Spain
| | | | - Rocío Gallego-Durán
- Unidad de Enfermedades Digestivas Hospitales Virgen Macarena-Virgen del Rocío; Instituto de Biomedicina de Sevilla, Universidad de Sevilla; Seville Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd); Madrid Spain
| | - Bernat Soria
- Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER); Universidad Pablo Olavide; Seville Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM); Madrid Spain
| | - Baukje de Roos
- Rowett Institute of Nutrition and Health; University of Aberdeen; Aberdeen; UK
| | - Manuel Romero Gómez
- Unidad de Enfermedades Digestivas Hospitales Virgen Macarena-Virgen del Rocío; Instituto de Biomedicina de Sevilla, Universidad de Sevilla; Seville Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd); Madrid Spain
| | - Franz Martín
- Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER); Universidad Pablo Olavide; Seville Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM); Madrid Spain
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Sun HY, Lin CC, Tsai PJ, Tsai WJ, Lee JC, Tsao CW, Cheng PN, Wu IC, Chiu YC, Chang TT, Young KC. Lipoprotein lipase liberates free fatty acids to inhibit HCV infection and prevent hepatic lipid accumulation. Cell Microbiol 2016; 19. [PMID: 27665576 DOI: 10.1111/cmi.12673] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Revised: 09/15/2016] [Accepted: 09/20/2016] [Indexed: 02/06/2023]
Abstract
Lipoprotein lipase (LPL) has been identified as an anti-hepatitis C virus (HCV) host factor, but the cellular mechanism remains elusive. Here, we investigated the cellular mechanism of LPL involving in anti-HCV. The functional activation of peroxisome proliferator-activated receptor (PPAR) α signal by LPL transducing into hepatocytes was investigated in HCV-infected cells, primary human hepatocytes, and in HCV-core transgenic mice. The result showed that the levels of transcriptional transactivity and nuclear translocation of PPARα in Huh7 cells and primary human hepatocytes were elevated by physiologically ranged LPL treatment of either very-low density lipoprotein or HCV particles. The LPL-induced hepatic PPARα activation was weakened by blocking the LPL enzymatic activity, and by preventing the cellular uptake of free unsaturated fatty acids with either albumin chelator or silencing of CD36 translocase. The knockdowns of PPARα and CD36 reversed the LPL-mediated suppression of HCV infection. Furthermore, treatment with LPL, like the direct activation of PPARα, not only reduced the levels of apolipoproteins B, E, and J, which are involved in assembly and release of HCV virions, but also alleviated hepatic lipid accumulation induced by core protein. HCV-core transgenic mice exhibited more hepatic miR-27b, which negatively regulates PPARα expression, than did the wild-type controls. The induction of LPL activity by fasting in the core transgenic mice activated PPARα downstream target genes that are involved in fatty acid β-oxidation. Taken together, our study reveals dual beneficial outcomes of LPL in anti-HCV and anti-steatosis and shed light on the control of chronic hepatitis C in relation to LPL modulators.
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Affiliation(s)
- Hung-Yu Sun
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chun-Chieh Lin
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Pei-Ju Tsai
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Wei-Jen Tsai
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Jin-Ching Lee
- Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chiung-Wen Tsao
- Department of Nursing, Chung Hwa University of Medical Technology, Tainan, Taiwan
| | - Pin-Nan Cheng
- Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - I-Chin Wu
- Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yen-Cheng Chiu
- Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Ting-Tsung Chang
- Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Kung-Chia Young
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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