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Kim D, Cholankeril G, Ahmed A. Association between Body Fat Distribution and Nonalcoholic Fatty Liver Disease/Fibrosis Based on Race/Ethnicity. J Obes Metab Syndr 2024; 33:326-336. [PMID: 39428122 PMCID: PMC11704218 DOI: 10.7570/jomes24005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 05/31/2024] [Accepted: 06/23/2024] [Indexed: 10/22/2024] Open
Abstract
BACKGROUND Body fat distribution may impact nonalcoholic fatty liver disease (NAFLD) and significant fibrosis differently according to race/ethnicity. We determined the relationship between body fat distribution and NAFLD/significant fibrosis according to race/ethnicity. METHODS A cross-sectional study of 2,395 participants used the National Health and Nutrition Examination Survey 2017 to 2018. NAFLD and significant fibrosis (≥F2) were defined by controlled attenuation parameter scores and liver stiffness measurements on transient elastography, respectively. Visceral and subcutaneous fat volumes were defined by dual-energy X-ray absorptiometry. RESULTS The odds ratio (OR) for NAFLD per 1-standard deviation in visceral fat volume and subcutaneous fat volume was 2.05 (95% confidence interval [CI], 1.36 to 3.09) and 1.48 (95% CI, 1.04 to 2.09) in total population, respectively. Visceral fat in non-Hispanic Blacks had the highest odds for NAFLD (OR, 2.86; 95% CI, 1.45 to 5.62), and non-Hispanic Whites (OR, 2.29; 95% CI, 1.19 to 4.40) and non-Hispanic Asians (OR, 1.61; 95% CI, 1.13 to 2.29) were in order. Significant associations between subcutaneous fat volume (OR, 2.10; 95% CI, 1.34 to 3.29; P=0.003) or visceral fat volume (OR, 1.35; 95% CI, 1.05 to 1.73; P=0.023) and significant fibrosis were noted among individuals with NAFLD. Hispanics had the highest odds for NAFLD-associated significant fibrosis (OR, 2.74; 95% CI, 1.32 to 5.70 per 1-standard deviation in subcutaneous fat volume), and non-Hispanic Whites (OR, 2.35; 95% CI, 1.11 to 4.98) and non-Hispanic Asians (OR, 2.01; 95% CI, 1.01 to 4.01) were in order. CONCLUSION Visceral adiposity was associated with NAFLD and significant fibrosis despite the association of subcutaneous adiposity in NAFLD and significant fibrosis. Racial/ethnic differences in the association between body fat distribution on NAFLD and significant fibrosis were noted.
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Affiliation(s)
- Donghee Kim
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
| | - George Cholankeril
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Aijaz Ahmed
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
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2
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Shen W, Middleton MS, Cunha GM, Delgado TI, Wolfson T, Gamst A, Fowler KJ, Alazraki A, Trout AT, Ohliger MA, Shah SN, Bashir MR, Kleiner DE, Loomba R, Neuschwander-Tetri BA, Sanyal AJ, Zhou J, Sirlin CB, Lavine JE. Changes in abdominal adipose tissue depots assessed by MRI correlate with hepatic histologic improvement in non-alcoholic steatohepatitis. J Hepatol 2023; 78:238-246. [PMID: 36368598 PMCID: PMC9852022 DOI: 10.1016/j.jhep.2022.10.027] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 10/10/2022] [Accepted: 10/12/2022] [Indexed: 11/09/2022]
Abstract
BACKGROUND & AIMS Non-alcoholic steatohepatitis (NASH) is prevalent in adults with obesity and can progress to cirrhosis. In a secondary analysis of prospectively acquired data from the multicenter, randomized, placebo-controlled FLINT trial, we investigated the relationship between reduction in adipose tissue compartment volumes and hepatic histologic improvement. METHODS Adult participants in the FLINT trial with paired liver biopsies and abdominal MRI exams at baseline and end-of-treatment (72 weeks) were included (n = 76). Adipose tissue compartment volumes were obtained using MRI. RESULTS Treatment and placebo groups did not differ in baseline adipose tissue volumes, or in change in adipose tissue volumes longitudinally (p = 0.107 to 0.745). Deep subcutaneous adipose tissue (dSAT) and visceral adipose tissue volume reductions were associated with histologic improvement in NASH (i.e., NAS [non-alcoholic fatty liver disease activity score] reductions of ≥2 points, at least 1 point from lobular inflammation and hepatocellular ballooning, and no worsening of fibrosis) (p = 0.031, and 0.030, respectively). In a stepwise logistic regression procedure, which included demographics, treatment group, baseline histology, baseline and changes in adipose tissue volumes, MRI hepatic proton density fat fraction (PDFF), and serum aminotransferases as potential predictors, reductions in dSAT and PDFF were associated with histologic improvement in NASH (regression coefficient = -2.001 and -0.083, p = 0.044 and 0.033, respectively). CONCLUSIONS In adults with NASH in the FLINT trial, those with greater longitudinal reductions in dSAT and potentially visceral adipose tissue volumes showed greater hepatic histologic improvements, independent of reductions in hepatic PDFF. CLINICAL TRIAL NUMBER NCT01265498. IMPACT AND IMPLICATIONS Although central obesity has been identified as a risk factor for obesity-related disorders including insulin resistance and cardiovascular disease, the role of central obesity in non-alcoholic steatohepatitis (NASH) warrants further clarification. Our results highlight that a reduction in central obesity, specifically deep subcutaneous adipose tissue and visceral adipose tissue, may be related to histologic improvement in NASH. The findings from this analysis should increase awareness of the importance of lifestyle intervention in NASH for clinical researchers and clinicians. Future studies and clinical practice may design interventions that assess the reduction of deep subcutaneous adipose tissue and visceral adipose tissue as outcome measures, rather than simply weight reduction.
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Affiliation(s)
- Wei Shen
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA;; Institute of Human Nutrition, College of Physicians & Surgeons, Columbia University Irving Medical Center; NY, USA;; Columbia Magnetic Resonance Research Center (CMRRC), Columbia University, USA.
| | - Michael S Middleton
- Liver Imaging Group, Department of Radiology, UCSD School of Medicine, San Diego, CA, USA
| | | | - Timoteo I Delgado
- Liver Imaging Group, Department of Radiology, UCSD School of Medicine, San Diego, CA, USA
| | - Tanya Wolfson
- Computational and Applied Statistics Laboratory (CASL), San Diego Supercomputer Center at UCSD, San Diego, CA, USA
| | - Anthony Gamst
- Computational and Applied Statistics Laboratory (CASL), San Diego Supercomputer Center at UCSD, San Diego, CA, USA;; Department of Mathematics, UCSD, San Diego, CA, USA
| | - Kathryn J Fowler
- Liver Imaging Group, Department of Radiology, UCSD School of Medicine, San Diego, CA, USA
| | - Adina Alazraki
- Emory University School of Medicine, Department of Radiology and Imaging Sciences and Children's Healthcare of Atlanta, Atlanta, GA, USA
| | - Andrew T Trout
- Department of Radiology, Cincinnati Children's Hospital Medical Center and Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Michael A Ohliger
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA
| | - Shetal N Shah
- Section of Abdominal Imaging and Nuclear Medicine Department, Imaging Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Mustafa R Bashir
- Department of Radiology, Duke University Medical Center, Durham, North Carolina, USA;; Center for Advanced Magnetic Resonance Development, (CAMRD), Department of Radiology, Duke University Medical Center, Durham, NC, USA;; Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - David E Kleiner
- Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA
| | - Rohit Loomba
- NAFLD Research Center, Division of Gastroenterology, Department of Medicine, University of California-San Diego, La Jolla, CA, USA
| | | | | | - Jane Zhou
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA
| | - Claude B Sirlin
- Liver Imaging Group, Department of Radiology, UCSD School of Medicine, San Diego, CA, USA
| | - Joel E Lavine
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA;; Institute of Human Nutrition, College of Physicians & Surgeons, Columbia University Irving Medical Center; NY, USA
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Flessa CM, Nasiri-Ansari N, Kyrou I, Leca BM, Lianou M, Chatzigeorgiou A, Kaltsas G, Kassi E, Randeva HS. Genetic and Diet-Induced Animal Models for Non-Alcoholic Fatty Liver Disease (NAFLD) Research. Int J Mol Sci 2022; 23:15791. [PMID: 36555433 PMCID: PMC9780957 DOI: 10.3390/ijms232415791] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 12/05/2022] [Accepted: 12/10/2022] [Indexed: 12/15/2022] Open
Abstract
A rapidly increasing incidence of non-alcoholic fatty liver disease (NAFLD) is noted worldwide due to the adoption of western-type lifestyles and eating habits. This makes the understanding of the molecular mechanisms that drive the pathogenesis of this chronic disease and the development of newly approved treatments of utmost necessity. Animal models are indispensable tools for achieving these ends. Although the ideal mouse model for human NAFLD does not exist yet, several models have arisen with the combination of dietary interventions, genetic manipulations and/or administration of chemical substances. Herein, we present the most common mouse models used in the research of NAFLD, either for the whole disease spectrum or for a particular disease stage (e.g., non-alcoholic steatohepatitis). We also discuss the advantages and disadvantages of each model, along with the challenges facing the researchers who aim to develop and use animal models for translational research in NAFLD. Based on these characteristics and the specific study aims/needs, researchers should select the most appropriate model with caution when translating results from animal to human.
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Affiliation(s)
- Christina-Maria Flessa
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
| | - Narjes Nasiri-Ansari
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Ioannis Kyrou
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
- Research Institute for Health and Wellbeing, Coventry University, Coventry CV1 5FB, UK
- Aston Medical School, College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK
- Laboratory of Dietetics and Quality of Life, Department of Food Science and Human Nutrition, School of Food and Nutritional Sciences, Agricultural University of Athens, 11855 Athens, Greece
| | - Bianca M. Leca
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
| | - Maria Lianou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Antonios Chatzigeorgiou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Gregory Kaltsas
- Endocrine Unit, 1st Department of Propaedeutic Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Eva Kassi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Endocrine Unit, 1st Department of Propaedeutic Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Harpal S. Randeva
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
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4
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Phung HH, Lee CH. Mouse models of nonalcoholic steatohepatitis and their application to new drug development. Arch Pharm Res 2022; 45:761-794. [DOI: 10.1007/s12272-022-01410-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Accepted: 10/10/2022] [Indexed: 11/05/2022]
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5
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Chang E, Chang JS, Kong ID, Baik SK, Kim MY, Park KS. Multidimensional Biomarker Analysis Including Mitochondrial Stress Indicators for Nonalcoholic Fatty Liver Disease. Gut Liver 2021; 16:171-189. [PMID: 34420934 PMCID: PMC8924798 DOI: 10.5009/gnl210106] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 06/15/2021] [Accepted: 06/22/2021] [Indexed: 11/22/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is accompanied by a complex and multifactorial pathogenesis with sequential progressions from inflammation to fibrosis and then to cancer. This heterogeneity interferes with the development of precise diagnostic and prognostic strategies for NAFLD. The current approach for the diagnosis of simple steatosis, steatohepatitis, and cirrhosis mainly consists of ultrasonography, magnetic resonance imaging, elastography, and various serological analyses. However, individual dry and wet biomarkers have limitations demanding an integrative approach for the assessment of disease progression. Here, we review diagnostic strategies for simple steatosis, steatohepatitis and hepatic fibrosis, followed by potential biomarkers associated with fat accumulation and mitochondrial stress. For mitochondrial stress indicators, we focused on fibroblast growth factor 21 (FGF21), growth differentiation factor 15 (GDF15), angiopoietin-related growth factor and mitochondrial-derived peptides. Each biomarker may not strongly indicate the severity of steatosis or steatohepatitis. Instead, multidimensional analysis of different groups of biomarkers based on pathogenic mechanisms may provide decisive diagnostic/prognostic information to develop a therapeutic plan for patients with NAFLD. For this purpose, mitochondrial stress indicators, such as FGF21 or GDF15, could be an important component in the multiplexed and contextual interpretation of NAFLD. Further validation of the integrative evaluation of mitochondrial stress indicators combined with other biomarkers is needed in the diagnosis/prognosis of NAFLD.
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Affiliation(s)
- Eunha Chang
- Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Jae Seung Chang
- Department of Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - In Deok Kong
- Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Soon Koo Baik
- Department of Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Moon Young Kim
- Department of Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Kyu-Sang Park
- Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea
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6
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Soret PA, Magusto J, Housset C, Gautheron J. In Vitro and In Vivo Models of Non-Alcoholic Fatty Liver Disease: A Critical Appraisal. J Clin Med 2020; 10:jcm10010036. [PMID: 33374435 PMCID: PMC7794936 DOI: 10.3390/jcm10010036] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 12/22/2020] [Accepted: 12/23/2020] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), including non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), represents the hepatic manifestation of obesity and metabolic syndrome. Due to the spread of the obesity epidemic, NAFLD is becoming the most common chronic liver disease and one of the principal indications for liver transplantation. However, no pharmacological treatment is currently approved to prevent the outbreak of NASH, which leads to fibrosis and cirrhosis. Preclinical research is required to improve our knowledge of NAFLD physiopathology and to identify new therapeutic targets. In the present review, we summarize advances in NAFLD preclinical models from cellular models, including new bioengineered platforms, to in vivo models, with a particular focus on genetic and dietary mouse models. We aim to discuss the advantages and limits of these different models.
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Affiliation(s)
- Pierre-Antoine Soret
- Centre de Recherche Saint-Antoine (CRSA), Sorbonne Université, Inserm, 75012 Paris, France; (P.-A.S.); (J.M.); (C.H.)
- Assistance Publique-Hôpitaux de Paris (AP-HP), Hepatology Department, Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, Saint-Antoine Hospital, 75012 Paris, France
| | - Julie Magusto
- Centre de Recherche Saint-Antoine (CRSA), Sorbonne Université, Inserm, 75012 Paris, France; (P.-A.S.); (J.M.); (C.H.)
- Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Université, Inserm, AP-HP, 75013 Paris, France
| | - Chantal Housset
- Centre de Recherche Saint-Antoine (CRSA), Sorbonne Université, Inserm, 75012 Paris, France; (P.-A.S.); (J.M.); (C.H.)
- Assistance Publique-Hôpitaux de Paris (AP-HP), Hepatology Department, Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, Saint-Antoine Hospital, 75012 Paris, France
- Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Université, Inserm, AP-HP, 75013 Paris, France
| | - Jérémie Gautheron
- Centre de Recherche Saint-Antoine (CRSA), Sorbonne Université, Inserm, 75012 Paris, France; (P.-A.S.); (J.M.); (C.H.)
- Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Université, Inserm, AP-HP, 75013 Paris, France
- Correspondence:
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7
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Li X, Wang H. Multiple organs involved in the pathogenesis of non-alcoholic fatty liver disease. Cell Biosci 2020; 10:140. [PMID: 33372630 PMCID: PMC7720519 DOI: 10.1186/s13578-020-00507-y] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 11/27/2020] [Indexed: 02/08/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) represents the leading cause of chronic liver disease worldwide and the anticipated health burden is huge. There are limited therapeutic approaches for NAFLD now. It’s imperative to get a better understanding of the disease pathogenesis if new treatments are to be discovered. As the hepatic manifestation of metabolic syndrome, this disease involves complex interactions between different organs and regulatory pathways. It’s increasingly clear that brain, gut and adipose tissue all contribute to NAFLD pathogenesis and development, in view of their roles in energy homeostasis. In the present review, we try to summarize currently available data regarding NAFLD pathogenesis and to lay a particular emphasis on the inter-organ crosstalk evidence.
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Affiliation(s)
- Xiaoyan Li
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Hua Wang
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China. .,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, 230032, China.
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8
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Karam HA, Bessa SS, Ali EMM, Diab T, Mohamed TM. The Inter-Relation between Leptin Receptor (Q223R) Gene Polymorphism and the Risk of Egyptian Patients with HCC. Asian Pac J Cancer Prev 2020; 21:3557-3565. [PMID: 33369452 PMCID: PMC8046304 DOI: 10.31557/apjcp.2020.21.12.3557] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Indexed: 11/25/2022] Open
Abstract
Background: The relationship of leptin (LEP) and polymorphism of leptin receptor (LEPR) were studied in patients with hepatocellular carcinoma (HCC) and compared with those with liver cirrhosis to find out the extent of the risk of LEPR on patients with HCC. Methods: Serum LEP level and LEPR Q223R gene polymorphism were determined in 300 patients with liver disease categorized equally into five groups’ healthy volunteers, patients with hepatitis C (HCV), patients with non-alcoholic steatohepatitis (NASH), liver cirrhosis and HCC. LEPR gene was amplified by polymerase chain reaction (PCR) then digested by the MSP1 restriction enzyme. Results: The isolated 212 bp of LEPR was sequenced. The serum LEP level was reduced in patients with cirrhotic and HCC. Serum LEP level had negatively correlated with both tumor grade and size in HCC patients. The data obtained from restriction fragment length polymorphismPCR and sequencing revealed the existence of a novel synonymous Q223R single nucleotide polymorphism (SNP) in exon 223 of LEPR gene (1137101). LEPR Gln223Arg, GG and GA genotypes were found in all studied groups. LEPR Gln223Arg, AA genotype was found in NASH, HCC, and control. LEPR Gln223Arg GA genotype is associated with some patients with HCC. Conclusion: GA genotype of LEPR Gln223Arg may be regarded as a probable genetic risk factor for Egyptian patients with HCC.
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Affiliation(s)
- Hala A Karam
- Department of Chemistry, Division of Biochemistry, Faculty of Science, Tanta University, Tanta, Egypt
| | - Sahar S Bessa
- Department of Internal Medicine, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Ehab M M Ali
- Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.,Department of Chemistry, Faculty of Science, Tanta University, Tanta, Egypt
| | - Thoria Diab
- Department of Chemistry, Division of Biochemistry, Faculty of Science, Tanta University, Tanta, Egypt
| | - Tarek M Mohamed
- Department of Chemistry, Division of Biochemistry, Faculty of Science, Tanta University, Tanta, Egypt
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9
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Plasma Krebs Cycle Intermediates in Nonalcoholic Fatty Liver Disease. J Clin Med 2020; 9:jcm9020314. [PMID: 31979094 PMCID: PMC7073566 DOI: 10.3390/jcm9020314] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 01/17/2020] [Accepted: 01/20/2020] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic liver disease (NAFLD) is manifested with a wide spectrum of clinical symptoms and is closely associated with the metabolic syndrome, inflammation, and mitochondrial dysfunction. Although the mechanism of mitochondrial dysfunction in NAFLD is still not fully elucidated, multiple studies have demonstrated evidence of molecular, biochemical, and biophysical mitochondrial abnormalities in NAFLD. Given the association between NAFLD and mitochondrial dysfunction, the aim of this study is to analyze circulating levels of Krebs cycle intermediates in a cohort of NAFLD-affected individuals and matching healthy controls and to correlate our findings with the liver function metrics. Standard serum biochemistry and Krebs cycle intermediates were analyzed in NAFLD (n = 22) and matched control (n = 67) cohorts. Circulating levels of isocitrate and citrate were significantly (p < 0.05) elevated in the NAFLD cohort of patients. The area under the curve (AUROC) for these two metabolites exhibited a moderate clinical utility. Correlations between plasma Krebs cycle intermediates and standard clinical plasma metrics were explored by Pearson’s correlation coefficient. The data obtained for plasma Krebs cycle intermediates suggest pathophysiological insights that link mitochondrial dysfunction with NAFLD. Our findings reveal that plasma isocitrate and citrate can discriminate between normal and NAFLD cohorts and can be utilized as noninvasive markers of mitochondrial dysfunction in NAFLD. Future studies with large populations at different NAFLD stages are warranted.
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10
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Yahaghi L, Ebrahim‐Habibi A, Hayati‐Roodbari N, Irani S, Yaghmaei P. A simple method for inducing nonalcoholic steatohepatitis with fibrosis. Animal Model Exp Med 2019; 2:282-290. [PMID: 31942560 PMCID: PMC6930990 DOI: 10.1002/ame2.12089] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 10/22/2019] [Accepted: 10/23/2019] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is increasingly occurring in sedentary people, and may progress to NASH and hepatocellular carcinoma. It is essential to design affordable animal models for the study of various diseases, including fatty liver, which was the aim of the study. In this study, a high-fat diet was devised that triggers NASH's animal model quickly and easily. High-fat diet (HFD) was used both with intra-mouth oral gavage and in combination with animal pellets. METHODS Twenty-four male C57BL/6J mice were divided into HFD and ND groups, which received a high-fat diet and a normal diet, respectively. At the end of the experiment (fourth week of treatment), body and liver weights, biochemical parameters, PPAR-α gene expression and histopathologic characteristics of the liver were evaluated. RESULTS During 4 weeks, body weight of mice did not show a significant increase in the HFD group compared to the ND group, while weight gain of the liver was significant. Histological assessment of the HFD group's liver confirmed NASH symptoms. In the HFD group, HDL-c, SOD, catalase, FRAP, adiponectin, and PPAR-α decreased significantly, and lipid profiles, hepatic enzymes, MDA, leptin, and TNF-α showed a significant increase compared to the ND group. CONCLUSION Our high-fat diet has successfully induced all aspects of NASH with fibrosis in 4 weeks, and with low cost.
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Affiliation(s)
- Leyla Yahaghi
- Department of Biology, Science and Research BranchIslamic Azad UniversityTehranIran
| | - Azadeh Ebrahim‐Habibi
- Biosensor Research CenterEndocrinology and Metabolism Molecular‐Cellular Sciences InstituteTehran University of Medical SciencesTehranIran
- Endocrinology and Metabolism Research CenterTehran University of Medical SciencesTehranIran
| | | | - Shiva Irani
- Department of Biology, Science and Research BranchIslamic Azad UniversityTehranIran
| | - Parichehreh Yaghmaei
- Department of Biology, Science and Research BranchIslamic Azad UniversityTehranIran
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11
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Huang M, Chen L, Shen Y, Chen J, Guo X, Xu N. Integrated mRNA and miRNA profile expression in livers of Jinhua and Landrace pigs. ASIAN-AUSTRALASIAN JOURNAL OF ANIMAL SCIENCES 2019; 32:1483-1490. [PMID: 31010989 PMCID: PMC6718901 DOI: 10.5713/ajas.18.0807] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Accepted: 02/26/2019] [Indexed: 01/29/2023]
Abstract
Objective To explore the molecular mechanisms of fat metabolism and deposition in pigs, an experiment was conducted to identify hepatic mRNAs and miRNAs expression and determine the potential interaction of them in two phenotypically extreme pig breeds. Methods mRNA and miRNA profiling of liver from 70-day Jinhua (JH) and Landrace (LD) pigs were performed using RNA sequencing. Blood samples were taken to detect results of serum biochemistry. Bioinformatics analysis were applied to construct differentially expressed miRNA-mRNA network. Results Serum total triiodothyronine and total thyroxine were significantly lower in Jinhua pigs, but the content of serum total cholesterol (TCH) and low-density lipoprotein cholesterol were strikingly higher. A total of 467 differentially expressed genes (DEGs) and 35 differentially expressed miRNAs (DE miRNAs) were identified between JH and LD groups. Gene ontology analysis suggested that DEGs were involved in oxidation-reduction, lipid biosynthetic and lipid metabolism process. Interaction network of DEGs and DE miRNAs were constructed, according to target prediction results. Conclusion We generated transcriptome and miRNAome profiles of liver from JH and LD pig breeds which represent distinguishing phenotypes of growth and metabolism. The potential miRNA-mRNA interaction networks may provide a comprehensive understanding in the mechanism of lipid metabolism. These results serve as a basis for further investigation on biological functions of miRNAs in the porcine liver.
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Affiliation(s)
- Minjie Huang
- Department of Animal Genetics and Breeding, College of Animal Science, Zhejiang University, Hangzhou 310058, China
| | - Lixing Chen
- Department of Animal Genetics and Breeding, College of Animal Science, Zhejiang University, Hangzhou 310058, China
| | - Yifei Shen
- Department of Animal Genetics and Breeding, College of Animal Science, Zhejiang University, Hangzhou 310058, China
| | - Jiucheng Chen
- Department of Animal Genetics and Breeding, College of Animal Science, Zhejiang University, Hangzhou 310058, China
| | - Xiaoling Guo
- Department of Animal Genetics and Breeding, College of Animal Science, Zhejiang University, Hangzhou 310058, China
| | - Ningying Xu
- Department of Animal Genetics and Breeding, College of Animal Science, Zhejiang University, Hangzhou 310058, China
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12
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Cernea S, Roiban AL, Both E, Huţanu A. Serum leptin and leptin resistance correlations with NAFLD in patients with type 2 diabetes. Diabetes Metab Res Rev 2018; 34:e3050. [PMID: 30052309 DOI: 10.1002/dmrr.3050] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2018] [Revised: 07/08/2018] [Accepted: 07/18/2018] [Indexed: 12/23/2022]
Abstract
AIMS Leptin/leptin resistance has been suggested to play a role in nonalcoholic fatty liver disease (NAFLD), and therefore we investigated the correlation of leptin/leptin-receptor system with markers of hepatic steatosis (HS) and fibrosis (HF) in patients with type 2 diabetes (T2D). MATERIALS AND METHODS In 159 T2D subjects with disease duration of 6.0 (0.0-27.0) years, HS was evaluated by semi-quantitative ultrasonographic scores and by clinical/biochemical variables: Fatty liver index and Hepatic steatosis index. HF was evaluated by NAFLD fibrosis score (NAFLD-FS). Serum leptin and leptin receptor (sObR) concentrations were measured and leptin resistance estimated by Free Leptin Index (FLpI). Both simple and multiple correlations between the HS and HF with the three parameters of interest were examined. RESULTS Leptin levels and FLpI correlated with diabetes duration (0.25 [95%CI: 0.09-0.39] and 0.24 [95%CI: 0.08-0.39]; P < 0.01 for both). 76.1% of T2D patients had HS and 29% had HF. The univariate analysis indicated positive correlations of HS indexes with serum leptin, FLpI, and negative correlations with serum sObR (P < 0.0001 for all). In the multiple regression analysis leptin, sObR, FLpI, waist-to-hip ratio, HbA1c, lipids, and HOMA-IR correlated independently with HS (P < 0.0001 for all). Although the univariate analyses indicated weak correlations of NAFLD-FS with leptin, sObR, and FLpI, in the multiple regression analyses, only age and waist independently predicted HF. CONCLUSION In patients with T2D, HS correlated positively with serum leptin and leptin resistance, and negatively with sObR, along with variables of adiposity and metabolic control, but neither of them made a significant contribution to HF.
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Affiliation(s)
- Simona Cernea
- Department M3/Internal Medicine IV, University of Medicine and Pharmacy of Tîrgu Mureş, Tîrgu Mureş, Romania
- Diabetes, Nutrition, and Metabolic Diseases Outpatient Unit, Emergency County Clinical Hospital Tîrgu Mureş, Tîrgu Mureş, Romania
| | - Andrada Larisa Roiban
- Emergency County Clinical Hospital Tîrgu Mureş, Tîrgu Mureş, Romania
- University of Medicine and Pharmacy of Tîrgu Mureș, Tîrgu Mureş, Romania
| | - Emőke Both
- Emergency County Clinical Hospital Tîrgu Mureş, Tîrgu Mureş, Romania
| | - Adina Huţanu
- Department of Laboratory Medicine, University of Medicine and Pharmacy of Tîrgu Mureș, Tîrgu Mureş, Romania
- Center for Advanced Medical and Pharmaceutical Research, University of Medicine and Pharmacy of Tîrgu Mureș, Tîrgu Mureş, Romania
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13
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Rotundo L, Persaud A, Feurdean M, Ahlawat S, Kim HS. The Association of leptin with severity of non-alcoholic fatty liver disease: A population-based study. Clin Mol Hepatol 2018; 24:392-401. [PMID: 30068065 PMCID: PMC6313023 DOI: 10.3350/cmh.2018.0011] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Accepted: 06/10/2018] [Indexed: 02/06/2023] Open
Abstract
Background/Aims Leptin is associated with metabolic disorders, which predispose one to non-alcoholic fatty liver disease (NAFLD). The role of leptin in NAFLD pathogenesis is not fully understood. We aim to investigate the association between serum leptin level and severity of NAFLD using U.S. nationally representative data. Methods Data were obtained from the United States Third National Health and Nutrition Examination Survey. NAFLD was defined by ultrasound detection and severity of hepatic steatosis in the absence of other liver diseases. The severity of hepatic fibrosis was determined by NAFLD fibrosis score (NFS). We used multivariate survey-weighted generalized logistic regression to evaluate the association between leptin level and the degree of NAFLD. We also performed subgroup analyses by body mass index (lean vs. classic NAFLD). Results Among 4,571 people, 1,610 (35%) had NAFLD. By ultrasound findings, there were 621 people with mild, 664 with moderate, and 325 with severe steatosis. There were 885 people with low NFS (<-1.455, no significant fibrosis), 596 with intermediate NFS, and 129 with high NFS (>0.676, advanced fibrosis). Leptin levels for normal, mild, moderate and severe steatosis were 10.7±0.3 ng/mL, 12.1±0.7 ng/mL, 15.6±0.8 ng/mL, 16±1.0 ng/mL, respectively (trend P-value<0.001). Leptin levels for low, intermediate, and high NFS were 11.8±0.5 ng/mL, 15.6±0.8 ng/mL, 28.5±3.5ng/mL, respectively (trend P-value<0.001). This association remained significant even after adjusting for known demographic and metabolic risk factors. In the subgroup analysis, this association was only prominent in classic NAFLD, but not in lean NAFLD. Conclusions Serum leptin level is associated with the severity of NAFLD, especially in classic NAFLD patients.
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Affiliation(s)
- Laura Rotundo
- Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Alana Persaud
- Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Mirela Feurdean
- Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Sushil Ahlawat
- Department of Division of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Hyun-Seok Kim
- Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA.,Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, TX, USA
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14
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Jahn D, Kircher S, Hermanns HM, Geier A. Animal models of NAFLD from a hepatologist's point of view. Biochim Biophys Acta Mol Basis Dis 2018; 1865:943-953. [PMID: 29990551 DOI: 10.1016/j.bbadis.2018.06.023] [Citation(s) in RCA: 138] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Revised: 06/22/2018] [Accepted: 06/25/2018] [Indexed: 02/07/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disorder closely linked to obesity, hyperlipidemia and type 2 diabetes and is increasingly recognized as a major health problem in many parts of the world. While early stages of NAFLD are characterized by a bland accumulation of fat (steatosis) in hepatocytes, the disease can progress to non-alcoholic steatohepatitis (NASH) which involves chronic liver inflammation, tissue damage and fibrosis and can ultimately lead to end-stage liver disease including cirrhosis and cancer. As no approved pharmacological treatment for NAFLD exists today, there is an urgent need to identify promising pharmacological targets and develop future therapies. For this purpose, basic and translational research in NAFLD animal models is indispensable. While a large number of diverse animal models are currently used in the field, there is an ongoing challenge to identify those models that mirror human pathology the closest to allow good translation of obtained results into further clinical development. This review is meant to provide a concise overview of the most relevant NAFLD animal models currently available and will discuss the strengths and weaknesses of these models with regard to their comparability to human disease conditions.
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Affiliation(s)
- Daniel Jahn
- University Hospital Würzburg, Division of Hepatology, Würzburg, Germany.
| | - Stefan Kircher
- University of Würzburg, Institute of Pathology, Würzburg, Germany; Comprehensive Cancer Center Mainfranken (CCCMF), Würzburg, Germany
| | - Heike M Hermanns
- University Hospital Würzburg, Division of Hepatology, Würzburg, Germany
| | - Andreas Geier
- University Hospital Würzburg, Division of Hepatology, Würzburg, Germany
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15
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Kramer AS, Latham B, Diepeveen LA, Mou L, Laurent GJ, Elsegood C, Ochoa-Callejero L, Yeoh GC. InForm software: a semi-automated research tool to identify presumptive human hepatic progenitor cells, and other histological features of pathological significance. Sci Rep 2018; 8:3418. [PMID: 29467378 PMCID: PMC5821869 DOI: 10.1038/s41598-018-21757-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2017] [Accepted: 01/30/2018] [Indexed: 12/19/2022] Open
Abstract
Hepatic progenitor cells (HPCs) play an important regenerative role in acute and chronic liver pathologies. Liver disease research often necessitates the grading of disease severity, and pathologists’ reports are the current gold-standard for assessment. However, it is often impractical to recruit pathologists in large cohort studies. In this study we utilise PerkinElmer’s “InForm” software package to semi-automate the scoring of patient liver biopsies, and compare outputs to a pathologist’s assessment. We examined a cohort of eleven acute hepatitis samples and three non-alcoholic fatty liver disease (NAFLD) samples, stained with HPC markers (GCTM-5 and Pan Cytokeratin), an inflammatory marker (CD45), Sirius Red to detect collagen and haematoxylin/eosin for general histology. InForm was configured to identify presumptive HPCs, CD45+ve inflammatory cells, areas of necrosis, fat and collagen deposition (p < 0.0001). Hepatitis samples were then evaluated both by a pathologist using the Ishak-Knodell scoring system, and by InForm through customised algorithms. Necroinflammation as evaluated by a pathologist, correlated with InForm outputs (r2 = 0.8192, p < 0.05). This study demonstrates that the InForm software package provides a useful tool for liver disease research, allowing rapid, and objective quantification of the presumptive HPCs and identifies histological features that assist with assessing liver disease severity, and potentially can facilitate diagnosis.
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Affiliation(s)
- Anne S Kramer
- Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands and Centre for Medical Research, The University of Western Australia, Crawley, WA, Australia.,School of Molecular Sciences, The University of Western Australia, Crawley, WA, Australia.,Centre for Cell Therapy and Regenerative Medicine, School of Biomedical Sciences, The University of Western Australia, Crawley, WA, Australia
| | - Bruce Latham
- PathWest Laboratory Medicine WA, Fiona Stanley Hospital, Murdoch, WA, Australia
| | - Luke A Diepeveen
- Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands and Centre for Medical Research, The University of Western Australia, Crawley, WA, Australia
| | - Lingjun Mou
- WA Liver & Kidney Surgical Transplant Service, Sir Charles Gairdner Hospital, Nedlands, Australia
| | - Geoffrey J Laurent
- Centre for Cell Therapy and Regenerative Medicine, School of Biomedical Sciences, The University of Western Australia, Crawley, WA, Australia
| | - Caryn Elsegood
- School of Pharmacy and Biomedical Science, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA, Australia
| | - Laura Ochoa-Callejero
- Angiogenesis group, Oncology Area, Centre for Biomedical Research of La Rioja, Logroño, Spain
| | - George C Yeoh
- Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands and Centre for Medical Research, The University of Western Australia, Crawley, WA, Australia. .,School of Molecular Sciences, The University of Western Australia, Crawley, WA, Australia. .,Centre for Cell Therapy and Regenerative Medicine, School of Biomedical Sciences, The University of Western Australia, Crawley, WA, Australia.
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16
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Machado MV, Diehl AM. Pathogenesis of Nonalcoholic Fatty Liver Disease. ZAKIM AND BOYER'S HEPATOLOGY 2018:369-390.e14. [DOI: 10.1016/b978-0-323-37591-7.00025-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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17
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Xiong L, Ren F, Lv J, Zhang H, Guo H. Lactoferrin attenuates high-fat diet-induced hepatic steatosis and lipid metabolic dysfunctions by suppressing hepatic lipogenesis and down-regulating inflammation in C57BL/6J mice. Food Funct 2018; 9:4328-4339. [DOI: 10.1039/c8fo00317c] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Lactoferrin was reported to exert modulatory effects on lipid metabolism, but the regulatory mechanisms remain unclear.
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Affiliation(s)
- Ling Xiong
- Beijing Advanced Innovation Center for Food Nutrition and Human Health
- College of Food Science & Nutritional Engineering
- China Agricultural University
- Beijing 100083
- China
| | - Fazheng Ren
- Beijing Advanced Innovation Center for Food Nutrition and Human Health
- College of Food Science & Nutritional Engineering
- China Agricultural University
- Beijing 100083
- China
| | - Jiayi Lv
- Key Laboratory of Functional Dairy
- Co-constructed by the Ministry of Education and Beijing Government
- China Agricultural University
- Beijing 100083
- China
| | - Hao Zhang
- Beijing Advanced Innovation Center for Food Nutrition and Human Health
- College of Food Science & Nutritional Engineering
- China Agricultural University
- Beijing 100083
- China
| | - Huiyuan Guo
- Beijing Advanced Innovation Center for Food Nutrition and Human Health
- College of Food Science & Nutritional Engineering
- China Agricultural University
- Beijing 100083
- China
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18
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Nazish I, Ansari SH. Emblica officinalis - Anti-obesity activity. JOURNAL OF COMPLEMENTARY & INTEGRATIVE MEDICINE 2017; 15:/j/jcim.ahead-of-print/jcim-2016-0051/jcim-2016-0051.xml. [PMID: 29206643 DOI: 10.1515/jcim-2016-0051] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Accepted: 10/09/2017] [Indexed: 06/07/2023]
Abstract
Context Emblica officinalis Gaertn. (family-Phyllanthaceae) fruits, known commonly as amla, is extensively used in Indian traditional system of medicine for the treatment of various disorders. The ethanolic E. officinalis extract is reported to have various activity such as antidiabetic, antihyperlipidemic and antioxidant activity in experimental animals. Objective To evaluate anti-obesity effect of aqueous E. officinalis extract in murine model of high fat diet (HFD)-induced obesity. Materials and methods Male Wistar rats fed with HFD (20 g/day/rat, p.o) for a period of 42 days were used to induce obesity. Aqueous E. officinalis extract (20 mg/kg bw) administered orally to HFD-fed rats from day 8 to 50 days for a period of 42 days. Body weight gain, serum lipids, insulin and leptin parameters were measured. Results Oral feeding of the aqueous E. officinalis extract (20 mg/kg) to HFD-induced obese rats for a period of 42 days resulted in significant reduction in body weight gain, insulin, leptin, lipids as compared to rats fed HFD alone. Further, the extract also showed significant increase in high density lipoprotein (HDL-C) levels. Discussion and conclusions These results show that aqueous E. officinalis extract possess significant anti-obesity potential.
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Affiliation(s)
- Iram Nazish
- Department of Pharmacology, HK College of Pharmacy, Oshiwara, Mumbai, India
| | - Shahid H Ansari
- Department of Pharmacognosy and Phytochemistry, Faculty of Pharmacy, Hamdard University, Hamdard Nagar, New Delhi, India
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19
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Gong Z, Tas E, Yakar S, Muzumdar R. Hepatic lipid metabolism and non-alcoholic fatty liver disease in aging. Mol Cell Endocrinol 2017; 455:115-130. [PMID: 28017785 DOI: 10.1016/j.mce.2016.12.022] [Citation(s) in RCA: 98] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Revised: 09/23/2016] [Accepted: 12/16/2016] [Indexed: 02/06/2023]
Abstract
Aging is associated with dysregulation of glucose and lipid metabolism. Various factors that contribute to the dysregulation include both modifiable (e.g. obesity, insulin resistance) and non-modifiable risk factors (age-associated physiologic changes). Although there is no linear relationship between aging and prevalence of non-alcoholic fatty liver disease, current data strongly suggests that advanced age leads to more severe histological changes and poorer clinical outcomes. Hepatic lipid accumulation could lead to significant hepatic and systemic consequences including steatohepatitis, cirrhosis, impairment of systemic glucose metabolism and metabolic syndrome, thereby contributing to age-related diseases. Insulin, leptin and adiponectin are key regulators of the various physiologic processes that regulate hepatic lipid metabolism. Recent advances have expanded our understanding in this field, highlighting the role of novel mediators such as FGF 21, and mitochondria derived peptides. In this review, we will summarize the mediators of hepatic lipid metabolism and how they are altered in aging.
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Affiliation(s)
- Zhenwei Gong
- Department of Pediatrics, University of Pittsburgh School of Medicine, One Children's Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224, USA; Children's Hospital of Pittsburgh of UPMC, One Children's Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224, USA
| | - Emir Tas
- Children's Hospital of Pittsburgh of UPMC, One Children's Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224, USA
| | - Shoshana Yakar
- David B. Kriser Dental Center, Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, NY 10010, USA
| | - Radhika Muzumdar
- Department of Pediatrics, University of Pittsburgh School of Medicine, One Children's Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224, USA; Children's Hospital of Pittsburgh of UPMC, One Children's Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224, USA; Department of Cell Biology, University of Pittsburgh School of Medicine, 3500 Terrace Street, 5362 Biomedical Sciences Tower, Pittsburgh, PA 15261, USA.
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20
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Shouhed D, Steggerda J, Burch M, Noureddin M. The role of bariatric surgery in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Expert Rev Gastroenterol Hepatol 2017; 11:797-811. [PMID: 28712339 DOI: 10.1080/17474124.2017.1355731] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) affects between 25% and 33% of the population, is more common in obese individuals, and is the most common cause of chronic liver disease in the United States. However, despite rising prevalence, effective treatments remain limited. Areas covered: We performed a literature search across multiple databases (Pubmed, Medline, etc.) to identify significant original research and review articles to provide an up-to-date and concise overview of disease pathogenesis and diagnostic evaluation and to expand on available treatment options with a specific focus on the potential role of bariatric surgery. Here we provide the most comprehensive review of bariatric surgery for the management of NAFLD, noting benefits from different procedures and multiple reports showing improvements in steatosis, inflammation and fibrosis over the duration of follow-up. Expert commentary: The morbidity of NAFLD is significant as it may become the most common indication for liver transplantation within the next 5 years. In addition to known benefits of weight loss and diabetes resolution, bariatric surgery has the potential to halt and reverse disease progression and future controlled trials should be performed to further define its benefit in the treatment of NAFLD in morbidly obese patients.
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Affiliation(s)
- Daniel Shouhed
- a Department of Surgery , Cedars-Sinai Medical Center , Los Angeles , CA , USA.,b Division of Bariatric Surgery , Cedars-Sinai Medical Center , Los Angeles , CA , USA
| | - Justin Steggerda
- a Department of Surgery , Cedars-Sinai Medical Center , Los Angeles , CA , USA
| | - Miguel Burch
- a Department of Surgery , Cedars-Sinai Medical Center , Los Angeles , CA , USA.,b Division of Bariatric Surgery , Cedars-Sinai Medical Center , Los Angeles , CA , USA
| | - Mazen Noureddin
- c Fatty Liver Disease Program, Division of Digestive and Liver Diseases, Department of Medicine , Comprehensive Transplant Center, Cedars-Sinai Medical Center , Los Angeles , CA , USA
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21
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Yan C, Yang Q, Shen HM, Spitsbergen JM, Gong Z. Chronically high level of tgfb1a induction causes both hepatocellular carcinoma and cholangiocarcinoma via a dominant Erk pathway in zebrafish. Oncotarget 2017; 8:77096-77109. [PMID: 29100373 PMCID: PMC5652767 DOI: 10.18632/oncotarget.20357] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Accepted: 06/30/2017] [Indexed: 12/21/2022] Open
Abstract
Liver cancers including both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) have increased steadily with the prevalence of non-alcoholic steatohepatitis (NASH), but the underlying mechanism for the transition from NASH to liver cancers remains unclear. Here we first employed diet-induced NASH zebrafish and found that elevated level of satiety hormone, leptin, induced overexpression of tgfb1. Then we developed tgfb1a transgenic zebrafish for inducible, hepatocyte-specific expression. Interestingly, chronically high tgfb1a induction in hepatocytes could concurrently drive both HCC and CCA. Molecularly, oncogenicity of Tgfb1 in HCC was dependent on the switch of dominant activated signaling pathway from Smad to Erk in hepatocytes while concurrent activation of both Smad and Erk pathways in cholangiocytes was essential for Tgfb1-induced CCA. These findings pinpointed the novel role of Tgfb1 as a central regulator in the two major types of liver cancers, which was also supported by human liver disease samples.
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Affiliation(s)
- Chuan Yan
- Department of Biological Sciences, National University of Singapore, Singapore.,National University of Singapore Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore
| | - Qiqi Yang
- Department of Biological Sciences, National University of Singapore, Singapore
| | - Han-Ming Shen
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Jan M Spitsbergen
- Department of Microbiology, Oregon State University, Corvallis, OR, USA
| | - Zhiyuan Gong
- Department of Biological Sciences, National University of Singapore, Singapore.,National University of Singapore Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore
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22
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The pattern of IL-24/mda-7 and its cognate receptors expression following activation of human hepatic stellate cells. Biomed Rep 2017; 7:173-178. [PMID: 28804632 DOI: 10.3892/br.2017.931] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Accepted: 06/06/2017] [Indexed: 12/26/2022] Open
Abstract
Activation of hepatic stellate cells (HSCs) is the pivotal event during liver fibrosis. Interleukin (IL)-24/melanoma differentiation-associated gene-7 (mda-7) has attracted attention in the pathophysiology of some diseases, while its role in activation/suppression of human HSCs is still unclear. It is important to elucidate whether the expression levels of the IL-24/mda-7 protein and its receptors in HSC cells are changed following activation. LX-2 cells, a human hepatic stellate cell line were activated by a combination of leptin and serum starvation. The activation state was evaluated through measuring the mRNA expression of profibrotic molecules, collagen-I, TIMP metalloproteinase inhibitor-1 and transforming growth factor-β. The expression of IL-24/mda-7 was assessed in mRNA and protein levels by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and ELISA methods, respectively. Hence, the amount of IL-22R1 and IL-20R2 subunit expression was also compared in activated and normal LX-2 cells by RT-qPCR. The expression level of IL-24/mda-7 and its cognate receptors was detectable both in the normal and activated LX-2 cell line. Furthermore, in activated LX-2, a significant increase of IL24 expression either on IL-22R1 and IL-20R2 subunits was also noticeable in comparison to normal cells. The activation state of LX-2 cells caused significant changes of IL-24/mda-7 and its receptors expression. In addition, the elevation in IL-24/mda-7 during LX-2 cell activation, suggested that IL-24/mda-7 and its cognate receptors serve a possible role in the development of the fibrosis process. Therefore, IL-24/mda-7 and relevant signaling pathways may be employed as a target for fibrosis treatment.
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23
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Hadizadeh F, Faghihimani E, Adibi P. Nonalcoholic fatty liver disease: Diagnostic biomarkers. World J Gastrointest Pathophysiol 2017; 8:11-26. [PMID: 28573064 PMCID: PMC5437499 DOI: 10.4291/wjgp.v8.i2.11] [Citation(s) in RCA: 112] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2016] [Revised: 08/30/2016] [Accepted: 02/13/2017] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease is a common medical condition worldwide and its prevalence has increased notably in the past few years due to the increases in prevalence of obesity and metabolic syndrome. However, diagnosis of this disease is still a matter of debate because of disease variations and pathophysiologic alterations. Specific single markers have gained considerable attention recently, among them markers related to hepatic pathophysiology, inflammation, adipocytokines and so forth. But, it seems that no single marker is sufficient for diagnosis and staging of the disease, and applying a panel including different types of tests may be more useful.
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24
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Cazzo E, Pareja JC, Chaim EA. Nonalcoholic fatty liver disease and bariatric surgery: a comprehensive review. SAO PAULO MED J 2017; 135:277-295. [PMID: 28562737 PMCID: PMC10019840 DOI: 10.1590/1516-3180.2016.0306311216] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Accepted: 12/31/2016] [Indexed: 02/06/2023] Open
Abstract
CONTEXT AND OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) has been increasingly diagnosed worldwide and is now recognized as a source of public health concern. It comprises a wide spectrum of histological features that range from simple steatosis to severe forms of fibrosis, steatohepatitis and even cirrhosis. The impact of bariatric surgery on the course of NAFLD in individuals with obesity has been extensively studied. DESIGN AND SETTING: Narrative review; public university hospital. METHODS: A comprehensive review was conducted based on an online search on the electronic databases MEDLINE and LILACS using the MeSH terms "fatty liver" and "bariatric surgery". RESULTS: The exact mechanisms that lead to improvement in NAFLD following bariatric surgery are not completely understood. Since Roux-en-Y gastric bypass (RYGB) is the bariatric surgical procedure most performed worldwide, it is also the one from which the effects on NAFLD have been most studied, although there is also consistent evidence regarding the effects from gastric banding, sleeve gastrectomy and biliopancreatic diversions. CONCLUSION: According to the currently available evidence, bariatric surgery leads to significant improvement in NAFLD. Further research, especially by means of randomized controlled trials enrolling larger cohorts of individuals, is needed to determine the optimal procedure for this group of subjects.
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Affiliation(s)
- Everton Cazzo
- MD, MSc, PhD. Assistant Professor, Department of Surgery, Universidade Estadual de Campinas (UNICAMP), Campinas (SP), Brazil.
| | - José Carlos Pareja
- MD, PhD. Associate Professor, Department of Surgery, Universidade Estadual de Campinas (UNICAMP), Campinas (SP), Brazil.
| | - Elinton Adami Chaim
- MD, MSc, PhD. Full Professor, Department of Surgery, Universidade Estadual de Campinas (UNICAMP), Campinas, (SP), Brazil.
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25
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Dietrich CG, Rau M, Jahn D, Geier A. Changes in drug transport and metabolism and their clinical implications in non-alcoholic fatty liver disease. Expert Opin Drug Metab Toxicol 2017; 13:625-640. [PMID: 28359183 DOI: 10.1080/17425255.2017.1314461] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
INTRODUCTION The incidence of non-alcoholic fatty liver disease (NAFLD) is rising, especially in Western countries. Drug treatment in patients with NAFLD is common since it is linked to other conditions like diabetes, obesity, and cardiovascular disease. Consequently, changes in drug metabolism may have serious clinical implications. Areas covered: A literature search for studies in animal models or patients with obesity, fatty liver, non-alcoholic steatohepatitis (NASH) or NASH cirrhosis published before November 2016 was performed. After discussing epidemiology and animal models for NAFLD, we summarized both basic as well as clinical studies investigating changes in drug transport and metabolism in NAFLD. Important drug groups were assessed separately with emphasis on clinical implications for drug treatment in patients with NAFLD. Expert opinion: Given the frequency of NAFLD even today, a high degree of drug treatment in NAFLD patients appears safe and well-tolerated despite considerable changes in hepatic uptake, distribution, metabolism and transport of drugs in these patients. NASH causes changes in biliary excretion, systemic concentrations, and renal handling of drugs leading to alterations in drug efficacy or toxicity under specific circumstances. Future clinical drug studies should focus on this special patient population in order to avoid serious adverse events in NAFLD patients.
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Affiliation(s)
- Christoph G Dietrich
- a Bethlehem Center of Health , Department of Medicine , Stolberg/Rhineland , Germany
| | - Monika Rau
- b Division of Hepatology, Department of Medicine II , University of Würzburg , Würzburg , Germany
| | - Daniel Jahn
- b Division of Hepatology, Department of Medicine II , University of Würzburg , Würzburg , Germany
| | - Andreas Geier
- b Division of Hepatology, Department of Medicine II , University of Würzburg , Würzburg , Germany
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Bell A, Korourian S, Zeng H, Phelps J, Hakkak R. A diet containing a high- versus low-daidzein level does not protect against liver steatosis in the obese Zucker rat model. Food Funct 2017; 8:1293-1298. [PMID: 28244519 DOI: 10.1039/c6fo01772j] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The prevalence of obesity is increasing worldwide. Obesity increases the risk for non-alcoholic fatty liver disease through adipokine dysregulation and inflammation. Previously, we have reported that a high-isoflavone soy protein isolate (HISPI) diet is associated with significantly heavier body weights and reduced liver steatosis in obese Zucker rats (OZR) compared to a casein diet. The objective of this study was to investigate whether daidzein, a soy isoflavone in HISPI, is responsible for increased body weight gain or reduced liver steatosis. We hypothesized that a casein diet containing high daidzein (HD) compared to low daidzein (LD) would mitigate hepatic steatosis in female OZR. We used 19 five-week-old female OZR (fa/fa). Rats were randomly assigned to a modified AIN-93G diet containing HD (0.121 g kg-1 feed) or LD (0.01 g kg-1 feed). Rats were weighed twice weekly. Feed intake was measured once weekly, and kcal per kg of body weight was calculated. After 8 weeks, rats were sacrificed. Serum and livers were collected. Sections of the liver lobe were fixed in 10% buffered formalin and stained with hematoxylin and eosin. Steatosis was semiquantitated as a score of 1 to 4 based upon the relative degree of steatosis within hepatocytes: (1) <25%, (2) 25%-50%, (3) 50%-75%, and (4) >75%. Serum leptin and adiponectin were measured by ELISA. Our results did not show significant differences in mean liver steatosis scores, body weights, energy intake, and serum leptin and adiponectin levels between diet groups. In conclusion, daidzein may not be the main component of HISPI responsible for increasing body weight or reducing liver steatosis in OZR.
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Affiliation(s)
- Andrea Bell
- Arkansas Children's Research Institute, Little Rock, Arkansas, USA. and Department of Dietetics and Nutrition, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Soheila Korourian
- Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Huawei Zeng
- United States Department of Agriculture, Agricultural Research Service, Grand Forks Human Nutrition Research Center, Grand Forks, North Dakota, USA
| | - Joshua Phelps
- Department of Dietetics and Nutrition, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Reza Hakkak
- Arkansas Children's Research Institute, Little Rock, Arkansas, USA. and Department of Dietetics and Nutrition, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA and Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
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Ibrahim SH, Hirsova P, Malhi H, Gores GJ. Animal Models of Nonalcoholic Steatohepatitis: Eat, Delete, and Inflame. Dig Dis Sci 2016; 61:1325-36. [PMID: 26626909 PMCID: PMC4838538 DOI: 10.1007/s10620-015-3977-1] [Citation(s) in RCA: 169] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Accepted: 11/23/2015] [Indexed: 02/07/2023]
Abstract
With the obesity epidemic, nonalcoholic fatty liver disease (NAFLD) has become a public health problem with increasing prevalence. The mechanism of disease progression remains obscure and effective therapy is lacking. Therefore, there is a need to understand the pathogenic mechanisms responsible for disease development and progression in order to develop innovative therapies. To accomplish this goal, experimental animal models that recapitulate the human disease are necessary, especially, since causative mechanistic studies of NAFLD are more difficult or unethical to perform in humans. A large number of studies regarding the pathophysiology and treatment of nonalcoholic steatohepatitis (NASH) have been undertaken in mice to model human NAFLD and NASH. This review discusses the known dietary, genetic, and inflammation-based animal models of NASH described in recent years, with a focus on the major advances made in this field.
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Affiliation(s)
- Samar H Ibrahim
- Division of Pediatric Gastroenterology, Mayo Clinic, Rochester, MN, USA
| | - Petra Hirsova
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Harmeet Malhi
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Gregory J Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
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Robberecht H, Hermans N. Biomarkers of Metabolic Syndrome: Biochemical Background and Clinical Significance. Metab Syndr Relat Disord 2016; 14:47-93. [PMID: 26808223 DOI: 10.1089/met.2015.0113] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Biomarkers of the metabolic syndrome are divided into four subgroups. Although dividing them in groups has some limitations, it can be used to draw some conclusions. In a first part, the dyslipidemias and markers of oxidative stress are discussed, while inflammatory markers and cardiometabolic biomarkers are reviewed in a second part. For most of them, the biochemical background and clinical significance are discussed, although here also a well-cut separation cannot always be made. Altered levels cannot always be claimed as the cause, risk, or consequence of the syndrome. Several factors are interrelated to each other and act in a concerted, antagonistic, synergistic, or modulating way. Most important conclusions are summarized at the end of every reviewed subgroup. Genetic biomarkers or influences of various food components on concentration levels are not included in this review article.
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Affiliation(s)
- Harry Robberecht
- Department of Pharmaceutical Sciences, NatuRA (Natural Products and Food Research and Analysis), University of Antwerp , Wilrijk, Antwerp, Belgium
| | - Nina Hermans
- Department of Pharmaceutical Sciences, NatuRA (Natural Products and Food Research and Analysis), University of Antwerp , Wilrijk, Antwerp, Belgium
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Polyzos SA, Aronis KN, Kountouras J, Raptis DD, Vasiloglou MF, Mantzoros CS. Circulating leptin in non-alcoholic fatty liver disease: a systematic review and meta-analysis. Diabetologia 2016; 59:30-43. [PMID: 26407715 DOI: 10.1007/s00125-015-3769-3] [Citation(s) in RCA: 184] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2015] [Accepted: 09/07/2015] [Indexed: 12/21/2022]
Abstract
AIMS/HYPOTHESIS Clinical data regarding circulating leptin levels in patients with non-alcoholic fatty liver disease (NAFLD) are conflicting. The purpose of this meta-analysis was to compare leptin levels between the following groups: patients with biopsy-proven NAFLD vs controls; simple steatosis (SS) patients vs controls; non-alcoholic steatohepatitis (NASH) patients vs controls and NASH patients vs SS patients. METHODS We performed a systematic search in PubMed, Scopus and the Cochrane Library. We analysed 33 studies, published between 1999 and 2014, including 2,612 individuals (775 controls and 1,837 NAFLD patients). RESULTS Higher circulating leptin levels were observed in NAFLD patients vs controls (standardised mean difference [SMD] 0.640; 95% CI 0.422, 0.858), SS patients vs controls (SMD 0.358; 95% CI 0.043, 0.673), NASH patients vs controls (SMD 0.617; 95% CI 0.403, 0.832) and NASH patients vs SS patients (SMD 0.209; 95% CI 0.023, 0.395). These results remained essentially unchanged after excluding studies involving paediatric or adolescent populations and/or individuals undergoing bariatric surgery. There was moderate-to-severe heterogeneity among studies in all comparisons, but no significant publication bias was detected. Meta-regression analysis demonstrated that BMI was inversely associated with leptin SMD and accounted for 26.5% (p = 0.014) and 32.7% (p = 0.021) of the between-study variance in the comparison between NASH patients and controls and NAFLD patients and controls, respectively. However, when bariatric studies were excluded, BMI did not significantly explain the between-study variance. CONCLUSIONS/INTERPRETATION Circulating leptin levels were higher in patients with NAFLD than in controls. Higher levels of circulating leptin were associated with increased severity of NAFLD, and the association remained significant after the exclusion of studies involving paediatric or adolescent populations and morbidly obese individuals subjected to bariatric surgery.
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Affiliation(s)
- Stergios A Polyzos
- Second Medical Clinic, Department of Medicine, Aristotle University of Thessaloniki, Ippokration Hospital, 49 Konstantinoupoleos, 546 42, Thessaloniki, Greece.
| | - Konstantinos N Aronis
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
- Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA, USA
| | - Jannis Kountouras
- Second Medical Clinic, Department of Medicine, Aristotle University of Thessaloniki, Ippokration Hospital, 49 Konstantinoupoleos, 546 42, Thessaloniki, Greece
| | - Dimitrios D Raptis
- Second Medical Clinic, Department of Medicine, Aristotle University of Thessaloniki, Ippokration Hospital, 49 Konstantinoupoleos, 546 42, Thessaloniki, Greece
| | - Maria F Vasiloglou
- Second Medical Clinic, Department of Medicine, Aristotle University of Thessaloniki, Ippokration Hospital, 49 Konstantinoupoleos, 546 42, Thessaloniki, Greece
| | - Christos S Mantzoros
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
- Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA, USA
- Section of Endocrinology, Boston VA Healthcare System, Harvard Medical School, Boston, MA, USA
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Tammen SA, Park LK, Dolnikowski GG, Ausman LM, Friso S, Choi SW. Hepatic DNA hydroxymethylation is site-specifically altered by chronic alcohol consumption and aging. Eur J Nutr 2015; 56:535-544. [PMID: 26578530 DOI: 10.1007/s00394-015-1098-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2015] [Accepted: 11/04/2015] [Indexed: 01/03/2023]
Abstract
PURPOSE Global DNA hydroxymethylation is markedly decreased in human cancers, including hepatocellular carcinoma, which is associated with chronic alcohol consumption and aging. Because gene-specific changes in hydroxymethylcytosine may affect gene transcription, giving rise to a carcinogenic environment, we determined genome-wide site-specific changes in hepatic hydroxymethylcytosine that are associated with chronic alcohol consumption and aging. METHODS Young (4 months) and old (18 months) male C57Bl/6 mice were fed either an ethanol-containing Lieber-DeCarli liquid diet or an isocaloric control diet for 5 weeks. Genomic and gene-specific hydroxymethylcytosine patterns were determined through hydroxymethyl DNA immunoprecipitation array in hepatic DNA. RESULTS Hydroxymethylcytosine patterns were more perturbed by alcohol consumption in young mice than in old mice (431 differentially hydroxymethylated regions, DhMRs, in young vs 189 DhMRs in old). A CpG island ~2.5 kb upstream of the glucocorticoid receptor gene, Nr3c1, had increased hydroxymethylation as well as increased mRNA expression (p = 0.015) in young mice fed alcohol relative to the control group. Aging alone also altered hydroxymethylcytosine patterns, with 331 DhMRs, but alcohol attenuated this effect. Aging was associated with a decrease in hydroxymethylcytosine ~1 kb upstream of the leptin receptor gene, Lepr, and decreased transcription of this gene (p = 0.029). Nr3c1 and Lepr are both involved in hepatic lipid homeostasis and hepatosteatosis, which may create a carcinogenic environment. CONCLUSIONS These results suggest that the location of hydroxymethylcytosine in the genome is site specific and not random, and that changes in hydroxymethylation may play a role in the liver's response to aging and alcohol.
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Affiliation(s)
- Stephanie A Tammen
- Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA.,Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA, USA
| | - Lara K Park
- Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA.,Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA, USA
| | - Gregory G Dolnikowski
- Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA.,Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA, USA
| | - Lynne M Ausman
- Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA.,Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA, USA
| | | | - Sang-Woon Choi
- Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA. .,Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA, USA. .,Chaum Life Center, CHA University School of Medicine, 442, Dosan-daero, Gangnam-gu, Seoul, 135-948, Korea.
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31
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Macaluso FS, Maida M, Petta S. Genetic background in nonalcoholic fatty liver disease: A comprehensive review. World J Gastroenterol 2015; 21:11088-11111. [PMID: 26494964 PMCID: PMC4607907 DOI: 10.3748/wjg.v21.i39.11088] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Revised: 06/11/2015] [Accepted: 09/02/2015] [Indexed: 02/06/2023] Open
Abstract
In the Western world, nonalcoholic fatty liver disease (NAFLD) is considered as one of the most significant liver diseases of the twenty-first century. Its development is certainly driven by environmental factors, but it is also regulated by genetic background. The role of heritability has been widely demonstrated by several epidemiological, familial, and twin studies and case series, and likely reflects the wide inter-individual and inter-ethnic genetic variability in systemic metabolism and wound healing response processes. Consistent with this idea, genome-wide association studies have clearly identified Patatin-like phosholipase domain-containing 3 gene variant I148M as a major player in the development and progression of NAFLD. More recently, the transmembrane 6 superfamily member 2 E167K variant emerged as a relevant contributor in both NAFLD pathogenesis and cardiovascular outcomes. Furthermore, numerous case-control studies have been performed to elucidate the potential role of candidate genes in the pathogenesis and progression of fatty liver, although findings are sometimes contradictory. Accordingly, we performed a comprehensive literature search and review on the role of genetics in NAFLD. We emphasize the strengths and weaknesses of the available literature and outline the putative role of each genetic variant in influencing susceptibility and/or progression of the disease.
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Monika P, Geetha A. The modulating effect of Persea americana fruit extract on the level of expression of fatty acid synthase complex, lipoprotein lipase, fibroblast growth factor-21 and leptin--A biochemical study in rats subjected to experimental hyperlipidemia and obesity. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2015; 22:939-945. [PMID: 26321743 DOI: 10.1016/j.phymed.2015.07.001] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/21/2014] [Revised: 06/25/2015] [Accepted: 07/01/2015] [Indexed: 06/04/2023]
Abstract
BACKGROUND Obesity is a multifactorial disorder which is closely associated with hyperlipidemia. Avocados are edible fruits traditionally consumed for various health benefits including body weight reduction. HYPOTHESIS/PURPOSE To determine the hypolipidemic and anti-obesity effect of hydro-alcoholic fruit extract of avocado (HFEA) in rats fed with high fat diet (HFD). STUDY DESIGN Male Sprague Dawley rats were divided into four groups. Groups 1 and 2 rats were fed with normal diet. Groups 3 and 4 rats were fed with HFD for 14 weeks. In addition, Groups 2 and 4 rats were co-administered with 100 mg/kg body weight of HFEA from 3rd week onwards. METHODS The HFEA was subjected to HPLC to quantify the major phytonutrients. Body mass index (BMI), adiposity index (ADI), total fat pad mass (TFP), blood lipid levels were determined in all the groups of rats. The mRNA expression of fatty acid synthase (FASN), lipoprotein lipase (LPL), fibroblast growth factor 21 (FGF21) and leptin was also assessed. RESULTS HFEA was found to contain flavonoids: rutin-141.79, quercetin-5.25, luteolin-165, phenolic compounds: gallic acid-198.57, ellagic acid-238.22, vanillic acid-4.79 and phytosterols: betasitosterol-70, stigmasterol-12.5 (mg/100 g). HFEA reduced BMI, ADI, TFP, blood cholesterol, triglycerides, and LDL in rats fed with HFD. Serum leptin was found reduced in HFEA co-administered rats. The mRNA expression of FASN, LPL, and leptin in subcutaneous and visceral adipose tissue was found to be significantly reduced in HFEA co-administered rats. The gene expression of fibroblast growth factor-21 (FGF21) was found to be significantly increased in HFEA treated rats when compared to HFD control rats. CONCLUSION The hypolipidemic effect of HFEA may be partly due to its modulating effect on endogenous fat synthesis and adiponectin formation through the transcription factor FGF21. The results also show that avocado fruit extract has profound influence on leptin activity, which controls satiety and hunger to regulate the food intake.
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Affiliation(s)
- Padmanabhan Monika
- Department of Biochemistry, Bharathi Women's College, Broadway, Chennai 600108, India
| | - Arumugam Geetha
- Department of Biochemistry, Bharathi Women's College, Broadway, Chennai 600108, India.
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Hamza N, Berke B, Cheze C, Marais S, Lorrain S, Abdouelfath A, Lassalle R, Carles D, Gin H, Moore N. Effect of Centaurium erythraea Rafn, Artemisia herba-alba Asso and Trigonella foenum-graecum L. on liver fat accumulation in C57BL/6J mice with high-fat diet-induced type 2 diabetes. JOURNAL OF ETHNOPHARMACOLOGY 2015; 171:4-11. [PMID: 26023031 DOI: 10.1016/j.jep.2015.05.027] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/13/2015] [Revised: 05/08/2015] [Accepted: 05/16/2015] [Indexed: 06/04/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Centaurium erythraea Rafn (CE), Artemisia herba-alba Asso (AHA) and Trigonella foenum-graecum L. (TFG) are traditionally used to treat type 2 diabetes in Algeria, previous studies have found that extracts of these plants were effective to treat or prevent experimental diabetes induced by high-fat diet (HFD). AIM OF THE STUDY Describe the additional effects of these extracts on lipid tissue deposition in HFD. MATERIALS AND METHODS Male C57BL/6J mice were fed with HFD to induce type 2 Diabetes. Groups of mice were given plant extracts orally at 2g/kg/bodyweight daily for 20 weeks during establishment of diabetes, or for 18 weeks after confirmation of diabetes at the 17th week. Liver and other tissue samples were stained with Oil Red O. RESULTS Liver steatosis was confirmed with HFD. CE, AHA and TFG extracts improved liver steatosis by the end of the preventive (20 weeks) and curative periods (35 weeks). This was most marked for CE extract (p<0.05), less so with TFG and AHA. No steatosis was found in other tissues. CONCLUSION CE extract had a clear hepatoprotective effect in this mouse model of diet-induced type 2 diabetes. AHA and TFG had a minimal or no significant effect on steatosis. Beyond its effect as an antidiabetic agent, CE may also be promising to prevent or treat non-alcoholic liver steatosis.
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Affiliation(s)
- Nawel Hamza
- Département de Pharmacologie, Université de Bordeaux, Bordeaux, France; Département de Nutrition, Université des frères Mentouri, INATAA, Constantine, Algerie.
| | - Bénédicte Berke
- Département de Pharmacologie, Université de Bordeaux, Bordeaux, France
| | - Catherine Cheze
- Département de Pharmacologie, Université de Bordeaux, Bordeaux, France
| | - Sébastien Marais
- Bordeaux Imaging Center, UMS 3420 CNRS, Université de Bordeaux, Bordeaux, France
| | - Simon Lorrain
- Département de Pharmacologie, Université de Bordeaux, Bordeaux, France
| | | | - Regis Lassalle
- Département de Pharmacologie, Université de Bordeaux, Bordeaux, France
| | - Dominique Carles
- Unité de pathologie fœtoplacentaire, Université de Bordeaux, CHU de Bordeaux, Hôpital Pellegrin, Bordeaux, France
| | - Henri Gin
- Service de Nutrition Diabétologie et Maladies Métaboliques, CHU de Bordeaux, Haut-Levèque, Bordeaux, France
| | - Nicholas Moore
- Département de Pharmacologie, Université de Bordeaux, Bordeaux, France.
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Sharma M, Mitnala S, Vishnubhotla RK, Mukherjee R, Reddy DN, Rao PN. The Riddle of Nonalcoholic Fatty Liver Disease: Progression From Nonalcoholic Fatty Liver to Nonalcoholic Steatohepatitis. J Clin Exp Hepatol 2015; 5:147-58. [PMID: 26155043 PMCID: PMC4491606 DOI: 10.1016/j.jceh.2015.02.002] [Citation(s) in RCA: 100] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2014] [Accepted: 02/09/2015] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver (NAFL) is an emerging global epidemic which progresses to nonalcoholic steatohepatitis (NASH) and cirrhosis in a subset of subjects. Various reviews have focused on the etiology, epidemiology, pathogenesis and treatment of NAFLD. This review highlights specifically the triggers implicated in disease progression from NAFL to NASH. The integrating role of genes, dietary factors, innate immunity, cytokines and gut microbiome have been discussed.
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Key Words
- AGE, Advanced glycation end products
- ALT, Alanine aminotransferase
- AMPK, AMP-activated protein Kinase
- APPL1 and 2, Adaptor protein 1 and 2
- ATP, Adenosine tri-phosphatase
- BMI, Basal Metabolic Index
- CD, Cluster of differentiation
- COL13A1, Collagen, type XIII, alpha 1
- DAMP, Damage assocauted molecular pattern molecules
- EFCAB4B, EF-hand calcium binding domain 4B
- FA, Fatty acid
- FDFT1, Farnesyl-diphosphate farnesyltransferase 1
- FFA, Free fatty acid
- GCKR, Glucokinase regulatory protein
- GLUT 5, Glucose transporter type 5
- GWAS, Genome wide association studies
- HDL, High density lipoprotein
- HMGB1, High-mobility group protein B1
- HOMA-IR, Homoestatic model assessment-insulin resistance
- HSC, Hepatic Stellate Cells
- Hh, Hedgehog
- IL6, Interleukin 6
- IR, Insulin Resistance
- KC, Kupffer Cells
- LPS, Lipopolysacharrides
- LYPLAL1, Lypophospholipase like 1
- MCP, Monocyte chemotactic protein
- NAD, Nicotinamide adenine dinucleotide
- NAFL, Nonalcoholic fatty liver
- NAFLD, Nonalcoholic fatty liver disease
- NASH, Nonalcoholic steatohepatitis
- NCAN, Neurocan gene
- NF-KB, Nuclear Factor Kappa B
- NK, Natural Killer
- NKL, Natural Killer T cells
- NLR, NOD like receptor
- NNMT, Nicotinamide N-methyltransferase gene
- OXLAM, Oxidized linolenic acid metabolite
- PAMP, Pathogen-associated Molecular pattern
- PARVB, Beta Parvin Gene
- PDGF, Platelet-derived growth factor
- PNPLA3
- PNPLA3, Patatin-like phospholipase domain-containing protein 3
- PPAR-α, Peroxisome proliferator activated receptor alpha
- PPP1R3B, Protein phosphatase 1 R3B
- PUFA, Poly unsaturated fatty acid
- PZP, Pregnancy-zone protein
- ROS, Reactive oxygen species
- SAMM, Sorting and assembly machinery component
- SCAP, SREBP cleavage-activating protein
- SFA, Saturated fatty acid
- SNP, Single nucleotide polymorphism
- SOCS3, Suppressor of cytokine signaling 3
- SOD2, Superoxide dismutase 2 gene
- SREBP-1C, Sterol regulatory Element—Binding Protein 1-C gene
- TLR, Toll like receptor
- TNF α, Tumor necrosis factor Alpha
- UCP3, Uncoupling protein 3 gene
- adiponectin
- cytokines
- gut microbiota
- lipotoxicity
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Affiliation(s)
- Mithun Sharma
- Department of Hepatology and Nutrition, Asian Institute of Gastroenterology, Hyderabad, Telangana, India,Address for correspondence: Mithun Sharma, Consultant Hepatologist, Asian Institute of Gastroenterology, 6-3-661, Red Rose Café Lane, Somajigudda, Hyderabad 500082, India. Tel.: +91 8790622655.
| | - Shasikala Mitnala
- Research Labs, Institute of Basic Sciences and Translational Research, Asian Healthcare Foundation, Asian Institute of Gastroenterology, Hyderabad, Telangana, India
| | - Ravi K. Vishnubhotla
- Department of Genetics, Asian Healthcare Foundation, Asian Institute of Gastroenterology, Hyderabad, Telangana, India
| | - Rathin Mukherjee
- Department of Molecular Biology, Asian Healthcare Foundation, Asian Institute of Gastroenterology, Hyderabad, Telangana, India
| | - Duvvur N. Reddy
- Department of Gastroenterology, Asian Healthcare Foundation, Asian Institute of Gastroenterology, Hyderabad, Telangana, India
| | - Padaki N. Rao
- Department of Hepatology and Nutrition, Asian Healthcare Foundation, Asian Institute of Gastroenterology, Hyderabad, Telangana, India
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Rachakonda VP, Reeves VL, Aljammal J, Wills RC, Trybula JS, DeLany JP, Kienesberger PC, Kershaw EE. Serum autotaxin is independently associated with hepatic steatosis in women with severe obesity. Obesity (Silver Spring) 2015; 23:965-72. [PMID: 25865747 PMCID: PMC4414671 DOI: 10.1002/oby.20960] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Accepted: 10/13/2014] [Indexed: 12/20/2022]
Abstract
OBJECTIVE Autotaxin (ATX) is an adipocyte-derived lysophospholipase that generates the lipid signaling molecule lysophosphatidic acid (LPA). The aim of this study was to determine the relationship between serum ATX and nonalcoholic fatty liver disease (NAFLD) in females with obesity. METHODS 101 nondiabetic women with obesity (age: 31.5-55.8 years; BMI: 35.0-64.5 kg/m2) were classified as having NAFLD (36.3%) or not having NAFLD (63.7%) based on the degree of hepatic steatosis on abdominal CT. Subjects were characterized for metabolic phenotype including measures of energy, glucose, and lipid homeostasis. Fasting serum adipokines and inflammatory markers were determined by ELISA. Linear regression analysis was used to determine features independently associated with NAFLD. RESULTS Subjects with and without NAFLD differed in several key features of metabolic phenotype including BMI, waist circumference, fasting glucose and insulin, HOMA-IR, VLDL, triglycerides, and ALT. Serum adipokines, including ATX and leptin, were higher in subjects with NAFLD. Serum ATX was significantly correlated with alkaline phosphatase, fasting glucose, fasting insulin, and HOMA-IR. Linear regression analysis revealed that serum triglycerides and log-transformed ATX were independently associated with hepatic steatosis. CONCLUSIONS Serum ATX may be a potential pathogenic factor and/or biomarker for NAFLD in nondiabetic women with obesity.
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Affiliation(s)
- Vikrant P. Rachakonda
- Division of Gastroenterology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Valerie L. Reeves
- Division of Endocrinology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Jules Aljammal
- Division of Endocrinology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Rachel C. Wills
- Division of Endocrinology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Joy S. Trybula
- Division of Endocrinology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - James P. DeLany
- Division of Endocrinology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Petra C. Kienesberger
- Department of Biochemistry and Molecular Biology, Dalhousie Medicine New Brunswick, Saint John, NB E2L 4L5 Canada
| | - Erin E. Kershaw
- Division of Endocrinology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
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Agilli M, Aydin FN, Cayci T, Kurt YG. Evaluation of leptin in subjects with type 2 diabetes mellitus. Scandinavian Journal of Clinical and Laboratory Investigation 2015; 75:434-5. [PMID: 25874480 DOI: 10.3109/00365513.2015.1033742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Affiliation(s)
- Mehmet Agilli
- Department of Biochemistry, Agri Military Hospital , Agri
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Agilli M, Ekinci S. Effect of Leptin on the Relationship Between Body Weight and Knee Osteoarthritis-a Methodologic Approach: Comment on the Article by Fowler-Brown et al. Arthritis Rheumatol 2015; 67:1141. [DOI: 10.1002/art.39010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Kalafateli M, Triantos C, Tsochatzis E, Michalaki M, Koutroumpakis E, Thomopoulos K, Kyriazopoulou V, Jelastopulu E, Burroughs A, Lambropoulou-Karatza C, Nikolopoulou V. Adipokines levels are associated with the severity of liver disease in patients with alcoholic cirrhosis. World J Gastroenterol 2015; 21:3020-3029. [PMID: 25780301 PMCID: PMC4356923 DOI: 10.3748/wjg.v21.i10.3020] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2014] [Revised: 10/31/2014] [Accepted: 12/14/2014] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the adipokine levels of leptin, adiponectin, resistin, visfatin, retinol-binding protein 4 (RBP4), apelin in alcoholic liver cirrhosis (ALC). METHODS Forty non-diabetic ALC patients [median age: 59 years, males: 35 (87.5%), Child-Pugh (CP) score: median 7 (5-12), CP A/B/C: 18/10/12, Model for End-stage Liver Disease (MELD): median 10 (6-25), follow-up: median 32.5 mo (10-43)] were prospectively included. The serum adipokine levels were estimated in duplicate by ELISA. Somatometric characteristics were assessed with tetrapolar bioelectrical impedance analysis. Pearson's rank correlation coefficient was used to assess possible associations with adipokine levels. Univariate and multivariate Cox regression analysis was used to determine independent predictors for overall survival. RESULTS Body mass index: median 25.9 (range: 20.1-39.3), fat: 23.4% (7.6-42.1), fat mass: 17.8 (5.49-45.4), free fat mass: 56.1 (39.6-74.4), total body water (TBW): 40.6 (29.8-58.8). Leptin and visfatin levels were positively associated with fat mass (P < 0.001/P = 0.027, respectively) and RBP4 with TBW (P = 0.025). Median adiponectin levels were significantly higher in CPC compared to CPA (CPA: 7.99 ± 14.07, CPB: 7.66 ± 3.48, CPC: 25.73 ± 26.8, P = 0.04), whereas median RBP4 and apelin levels decreased across the spectrum of disease severity (P = 0.006/P = 0.034, respectively). Following adjustment for fat mass, visfatin and adiponectin levels were significantly increased from CPA to CPC (both P < 0.001), whereas an inverse correlation was observed for both RBP4 and apelin (both P < 0.001). In the multivariate Cox regression analysis, only MELD had an independent association with overall survival (HR = 1.53, 95%CI: 1.05-2.32; P = 0.029). CONCLUSION Adipokines are associated with deteriorating liver function in a complex manner in patients with alcoholic liver cirrhosis.
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Wolfs MGM, Gruben N, Rensen SS, Verdam FJ, Greve JW, Driessen A, Wijmenga C, Buurman WA, Franke L, Scheja L, Koonen DPY, Shiri-Sverdlov R, van Haeften TW, Hofker MH, Fu J. Determining the association between adipokine expression in multiple tissues and phenotypic features of non-alcoholic fatty liver disease in obesity. Nutr Diabetes 2015; 5:e146. [PMID: 25664838 PMCID: PMC4338415 DOI: 10.1038/nutd.2014.43] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2014] [Revised: 09/28/2014] [Accepted: 11/15/2014] [Indexed: 12/20/2022] Open
Abstract
Objectives: Non-alcoholic fatty liver disease (NAFLD) is an obesity-associated disease, and in obesity adipokines are believed to be involved in the development of NAFLD. However, it is still not clear whether adipokines in the liver and/or adipose tissues can be related to the development of specific characteristics of NAFLD, such as steatosis and inflammation. We aimed to address this question by simultaneously examining the adipokine expression in three tissue types in obese individuals. Methods: We enrolled 93 severely obese individuals with NAFLD, varying from simple steatosis to severe non-alcoholic steatohepatitis. Their expression of 48 adipokines in the liver, visceral and subcutaneous adipose tissue (SAT) was correlated to their phenotypic features of NAFLD. We further determined whether the correlations were tissue specific and/or independent of covariates, including age, sex, obesity, insulin resistance and type 2 diabetes (T2D). Results: The expression of adipokines showed a liver- and adipose tissue-specific pattern. We identified that the expression of leptin, angiopoietin 2 (ANGPT2) and chemerin in visceral adipose tissue (VAT) was associated with different NAFLD features, including steatosis, ballooning, portal and lobular inflammation. In addition, the expression of tumor necrosis factor (TNF), plasminogen activator inhibitor type 1 (PAI-1), insulin-like growth factor 1 (somatomedin C) (IGF1) and chemokine (C-X-C motif) ligand 10 (CXCL10) in the liver tissue and the expression of interleukin 1 receptor antagonist (IL1RN) in both the liver and SAT were associated with NAFLD features. The correlations between ANGPT2 and CXCL10, and NAFLD features were dependent on insulin resistance and T2D, but for the other genes the correlation with at least one NAFLD feature remained significant after correcting for the covariates. Conclusions: Our results suggest that in obese individuals, VAT-derived leptin and chemerin, and hepatic expression of TNF, IGF1, IL1RN and PAI-1 are involved in the development of NAFLD features. Further, functional studies are warranted to establish a causal relationship.
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Affiliation(s)
- M G M Wolfs
- Molecular Genetics Section, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - N Gruben
- Molecular Genetics Section, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - S S Rensen
- Department of General Surgery, Maastricht University Medical Center, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht, The Netherlands
| | - F J Verdam
- Department of General Surgery, Maastricht University Medical Center, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht, The Netherlands
| | - J W Greve
- Department of General Surgery, Maastricht University Medical Center, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht, The Netherlands
| | - A Driessen
- 1] Department of Pathology, Maastricht University Medical Centre, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht, The Netherlands [2] Department of Pathology, University Hospital Antwerp, Edegem, Belgium
| | - C Wijmenga
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - W A Buurman
- School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands
| | - L Franke
- 1] Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands [2] Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, London, UK
| | - L Scheja
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - D P Y Koonen
- Molecular Genetics Section, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - R Shiri-Sverdlov
- Department of Molecular Genetics, Maastricht University, Maastricht, The Netherlands
| | - T W van Haeften
- 1] Molecular Genetics Section, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands [2] Department of Internal Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
| | - M H Hofker
- Molecular Genetics Section, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - J Fu
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Evaluation of leptin, thought as a cancer-related biomarker, in postmenopausal women. Cancer Causes Control 2015; 26:163-4. [DOI: 10.1007/s10552-014-0488-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2014] [Accepted: 10/28/2014] [Indexed: 10/24/2022]
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41
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Relationship between leptin and blood pressure in patients with multiple system atrophy. J Neurol Sci 2015; 348:284. [DOI: 10.1016/j.jns.2014.11.030] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2014] [Revised: 10/23/2014] [Accepted: 11/24/2014] [Indexed: 10/24/2022]
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Kim NH, Park SH. Evaluation of green pepper (Capsicum annuum L.) juice on the weight gain and changes in lipid profile in C57BL/6 mice fed a high-fat diet. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2015; 95:79-87. [PMID: 24723459 DOI: 10.1002/jsfa.6685] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/03/2012] [Revised: 04/18/2013] [Accepted: 04/03/2014] [Indexed: 06/03/2023]
Abstract
BACKGROUND Capsicum pepper (green pepper, Capsicum annuum L.), a natural product available in many countries, is considered to be a food additive, with healthful or medical applications. The aim of this study was to evaluate green pepper juice for its potential to reduce weight gain and to determine its effects on lipid profiles in C57BL/6 mice fed a high-fat diet. RESULTS Mice given a high-fat diet with green pepper juice gained significantly less weight and showed a significant decrease in serum triglycerides, total cholesterol, low density lipoproteins, and alanine aminotransferase compared to mice given only a high-fat diet (P < 0.05). Systolic and diastolic blood pressure, heart rate, and blood glucose levels (determined by using the intraperitoneal glucose tolerance test) in mice administered green pepper juice were similar to those in mice in the control group. In addition, abdominal fat volume (subcutaneous and visceral), which was quantified by using 4.7 T magnetic resonance imaging, including multi-slice spin-echo T2-weighted images, in mice administered a high-fat diet with green pepper juice tended to decrease compared to the fat volume of mice administered only a high-fat diet. CONCLUSION These results suggest that green pepper juice, as a drink, may possibly be helpful in reducing weight gain by regulating the levels of serum lipids.
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Affiliation(s)
- Na-Hyung Kim
- Institute for Metabolic disease, Wonkwang University, Iksan, 344-2, Republic of Korea; Graduate School of East-West Medical Science, Kyung Hee University, Yongin, 446-701, Republic of Korea
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Polyzos SA, Kountouras J, Mantzoros CS. Leptin in nonalcoholic fatty liver disease: a narrative review. Metabolism 2015; 64:60-78. [PMID: 25456097 DOI: 10.1016/j.metabol.2014.10.012] [Citation(s) in RCA: 163] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2014] [Revised: 10/12/2014] [Accepted: 10/16/2014] [Indexed: 02/06/2023]
Abstract
Leptin, the first described adipokine, interplays with hepatic metabolism. The aim of this review was to summarize available data on the association between leptin and nonalcoholic fatty liver disease (NAFLD). Leptin has a potential dual action on NAFLD experimental models, exerting a possible anti-steatotic, but also a proinflammatory and profibrogenic action. Observational clinical studies have shown higher or similar leptin levels between simple steatosis and nonalcoholic steatohepatitis (NASH) compared with controls. Interventional studies showed that circulating leptin diminishes together with body mass index after successful weight loss following lifestyle modifications or bariatric surgery. Studies providing evidence for the effect of other medications on leptin levels in NAFLD populations are limited and of low power. Data from small studies claim that recombinant leptin administration had a possibly beneficial effect on steatosis, but not fibrosis, in NAFLD patients with hypoleptinemia. Although the aforementioned dual leptin action has not yet been validated in humans, leptin administration in NAFLD patients with normoleptinemia or hyperleptinemia is discouraged. Further well-controlled studies in cautiously selected populations are needed to elucidate whether leptin has any prognostic and therapeutic role in NAFLD patients.
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Affiliation(s)
- Stergios A Polyzos
- Second Medical Clinic, Department of Medicine, Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki, Greece; Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
| | - Jannis Kountouras
- Second Medical Clinic, Department of Medicine, Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki, Greece
| | - Christos S Mantzoros
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
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Menezes CN, Raal F, Immelman A, Song E. The role of increased gastrointestinal alcohol production in patients with the metabolic syndrome: Implications for the pathogenesis of non-alcoholic fatty liver disease. JOURNAL OF ENDOCRINOLOGY METABOLISM AND DIABETES OF SOUTH AFRICA 2014. [DOI: 10.1080/22201009.2008.10872170] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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Sim MO, Ham JR, Lee HI, Seo KI, Lee MK. Long-term supplementation of umbelliferone and 4-methylumbelliferone alleviates high-fat diet induced hypertriglyceridemia and hyperglycemia in mice. Chem Biol Interact 2014; 216:9-16. [PMID: 24661945 DOI: 10.1016/j.cbi.2014.03.003] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2013] [Revised: 02/27/2014] [Accepted: 03/13/2014] [Indexed: 02/06/2023]
Abstract
This study was conducted to evaluate the effects of umbelliferone (UF) and 4-methylumbelliferone (mUF) on high-fat diet-induced hypertriglyceridemia and hyperglycemia in mice. The mice were assigned to normal control, high-fat control, and high-fat with UF or mUF groups. For UF or mUF groups, the high-fat diet was supplemented with UF or mUF at 0.02% (wt/wt) for 12weeks. Both UF and mUF significantly decreased plasma triglyceride, free fatty acid and glucose levels, adipocyte size, white adipose tissue weights, and hepatic phosphatidate phosphohydrolase activity and significantly increased plasma adiponectin levels and hepatic fatty acid β-oxidation activity compared with the high-fat control group. UF and mUF improved glucose intolerance and hepatic steatosis in the high-fat fed mice. Long-term high-fat diet intake induced an increase in hepatic CYP2E1 activity and lipid peroxide and cytosolic hydrogen peroxide contents and suppressed superoxide dismutase and glutathione peroxidase activities, which were reversed by UF and mUF supplementation. These results indicate that UF and mUF similarly ameliorate hypertriglyceridemia and hyperglycemia partly by modulating hepatic lipid metabolism and the antioxidant defense system along with increasing adiponectin levels.
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Affiliation(s)
- Mi-Ok Sim
- Department of Food and Nutrition, Sunchon National University, Suncheon 540-950, Republic of Korea
| | - Ju Ri Ham
- Department of Food and Nutrition, Sunchon National University, Suncheon 540-950, Republic of Korea
| | - Hae-In Lee
- Department of Food and Nutrition, Sunchon National University, Suncheon 540-950, Republic of Korea
| | - Kwon-Il Seo
- Department of Food and Nutrition, Sunchon National University, Suncheon 540-950, Republic of Korea
| | - Mi-Kyung Lee
- Department of Food and Nutrition, Sunchon National University, Suncheon 540-950, Republic of Korea.
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Involvement of DNA damage response pathways in hepatocellular carcinoma. BIOMED RESEARCH INTERNATIONAL 2014; 2014:153867. [PMID: 24877058 PMCID: PMC4022277 DOI: 10.1155/2014/153867] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/08/2013] [Revised: 01/23/2014] [Accepted: 03/25/2014] [Indexed: 12/16/2022]
Abstract
Hepatocellular carcinoma (HCC) has been known as one of the most lethal human malignancies, due to the difficulty of early detection, chemoresistance, and radioresistance, and is characterized by active angiogenesis and metastasis, which account for rapid recurrence and poor survival. Its development has been closely associated with multiple risk factors, including hepatitis B and C virus infection, alcohol consumption, obesity, and diet contamination. Genetic alterations and genomic instability, probably resulted from unrepaired DNA lesions, are increasingly recognized as a common feature of human HCC. Dysregulation of DNA damage repair and signaling to cell cycle checkpoints, known as the DNA damage response (DDR), is associated with a predisposition to cancer and affects responses to DNA-damaging anticancer therapy. It has been demonstrated that various HCC-associated risk factors are able to promote DNA damages, formation of DNA adducts, and chromosomal aberrations. Hence, alterations in the DDR pathways may accumulate these lesions to trigger hepatocarcinogenesis and also to facilitate advanced HCC progression. This review collects some of the most known information about the link between HCC-associated risk factors and DDR pathways in HCC. Hopefully, the review will remind the researchers and clinicians of further characterizing and validating the roles of these DDR pathways in HCC.
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Oleuropein prevents the progression of steatohepatitis to hepatic fibrosis induced by a high-fat diet in mice. Exp Mol Med 2014; 46:e92. [PMID: 24763197 PMCID: PMC3972787 DOI: 10.1038/emm.2014.10] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2013] [Revised: 11/11/2013] [Accepted: 11/11/2013] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is characterized by hepatocyte injury and inflammatory cell infiltration, which has been linked to peripheral insulin resistance and increased levels of triglycerides in the liver. The purposes of this study were to establish a mouse model of NASH by feeding mice a 60% high-fat diet (HFD) and to demonstrate the anti-fibrotic effects of oleuropein, which has been shown to have anti-oxidant and anti-inflammatory properties, in this HFD-induced mouse model of NASH. C57BL/6 mice were divided into three groups: a regular diet group (Chow), a HFD group and an oleuropein-supplemented HFD group (OSD), which was fed a 0.05% OSD for 6 months. The effects of oleuropein in this model were evaluated using biochemical, histological and molecular markers. The expression levels of alpha-smooth muscle actin (α-SMA)and collagen type I in the HFD and OSD groups were evaluated using real-time PCR and western blotting. The body weight, biochemical marker levels, nonalcoholic fatty liver disease activity score, homeostasis model of assessment-insulin resistance (HOMA-IR) and leptin levels observed in the HFD group at 9 and 12 months were higher than those observed in the Chow group. The HOMA-IR and leptin levels in the OSD group were decreased compared with the HFD group. In addition, α-SMA and collagen type I expression were decreased by oleuropein treatment. We established a NASH model induced by HFD and demonstrated that this model exhibits the histopathological features of NASH progressing to fibrosis. Our results suggest that oleuropein may be pharmacologically useful in preventing the progression of steatohepatitis and fibrosis and may be a promising agent for the treatment of NASH in humans.
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Baranova A, Randhawa M, Jarrar M, Younossi ZM. Adipokines and melanocortins in the hepatic manifestation of metabolic syndrome: nonalcoholic fatty liver disease. Expert Rev Mol Diagn 2014; 7:195-205. [PMID: 17331066 DOI: 10.1586/14737159.7.2.195] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Metabolic syndrome is associated with nonalcoholic fatty liver disease and its more aggressive form, nonalcoholic steatohepatitis. Adipokines produced by white adipose tissue possess broad physiological activity and play an important autocrine role in obesity-associated complications, including metabolic syndrome, nonalcoholic fatty liver disease and cardiovascular disease. Various adipokines may have beneficial or harmful effects. Other tissues, particularly stomach and intestine, produce active molecules that can influence the function of adipocytes and, possibly, the levels of adipokine secretion. In some cases, the production sites of these molecules remain unknown. The review focuses on our current understanding of the disease-related effects of the adipokines and the melanocortins on various peripheral tissues, and discusses some of their potential interactions with each other. Potential therapeutic applications are also considered.
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Affiliation(s)
- Ancha Baranova
- Center for Liver Diseases, Inova Fairfax Hospital, VA, USA.
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Mildner-Szkudlarz S, Bajerska J. Protective effect of grape by-product-fortified breads against cholesterol/cholic acid diet-induced hypercholesterolaemia in rats. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2013; 93:3271-3278. [PMID: 23584744 DOI: 10.1002/jsfa.6171] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/26/2012] [Revised: 01/29/2013] [Accepted: 04/12/2013] [Indexed: 11/06/2022]
Abstract
BACKGROUND New breads fortified with two different forms of grape by-products, namely dried powdered skins (PGP) and freeze-dried extract therefrom (EGP), were characterised and their protective effect against hypercholesterolaemia in rats was studied. RESULTS The phenolic compound profiles of supplemented breads were dominated by epicatechin and catechin together with appreciable amounts of dimeric procyanidins. Sensory evaluation of enhanced breads revealed that a maximum of 6% PGP or 1.4% EGP could be incorporated to prepare acceptable products. Intake of high-cholesterol/cholic acid diet containing 6% PGP- or 1.4% EGP-fortified bread increased fresh stool weight and significantly reduced protein and fat digestion but did not negatively affect animal growth. PGP- and EGP-fortified breads diminished the negative impact of high-cholesterol/cholic acid diet, lowering total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), lipid peroxidation, glucose and leptin levels, preventing visceral fat accumulation and increasing high-density lipoprotein cholesterol and plasma ferric-reducing antioxidant power levels. Since control bread feeding significantly lowered TC, LDL-C and lipid peroxidation compared with high-fat diet, it may suggested that not only grape by-products but also another components in bread were related to lipid metabolism. CONCLUSION These results demonstrate that intake of both PGP- and EGP-fortified sourdough mixed rye breads might contribute to a reduction of cardiovascular risk.
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Affiliation(s)
- Sylwia Mildner-Szkudlarz
- Department of Food Science and Nutrition, Poznań University of Life Sciences, Ul. Wojska Polskiego 28, PL-60-637, Poznan, Poland
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Kumar V, Bhandari U, Tripathi CD, Khanna G. Evaluation of antiobesity and cardioprotective effect of Gymnema sylvestre extract in murine model. Indian J Pharmacol 2013; 44:607-13. [PMID: 23112423 PMCID: PMC3480794 DOI: 10.4103/0253-7613.100387] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2011] [Revised: 06/25/2012] [Accepted: 07/01/2012] [Indexed: 12/23/2022] Open
Abstract
OBJECTIVE Obesity plays a central role in the insulin resistance syndrome, which is associated with hyperinsulinemia, hypertension, hyperlipidemia, type 2 diabetes mellitus, and an increased risk of atherosclerotic cardiovascular disease. The present study was done to assess the effect of Gymnema sylvestre extract (GSE) in the high fat diet (HFD)-induced cellular obesity and cardiac damage in Wistar rats. MATERIALS AND METHODS Adult male Wistar rats (150-200 g body weight) were used in this study. HFD was used to induce obesity. Body mass index, hemodynamic parameters, serum leptin, insulin, glucose, lipids, apolipoprotein levels, myocardial apoptosis, and antioxidant enzymes were assessed. Organ and visceral fat pad weights and histopathological studies were also carried out. RESULTS Oral feeding of HFD (20 g/day) for a period of 28 days resulted in a significant increase in body mass index, organ weights, visceral fat pad weight, cardiac caspase-3, cardiac DNA laddering (indicating apoptotic inter-nucleosomal DNA fragment), and lipid peroxide levels of cardiac tissues of rats. Further, mean arterial blood pressure, heart rate, serum leptin, insulin, LDH, LDL-C, total cholesterol, triglycerides, and apolipoprotein-B levels were enhanced significantly, whereas serum HDL-C, apoliporotein-A1 levels, and cardiac Na(+) K(+) ATPase, antioxidant enzymes levels were significantly decreased. Furthermore, treatment with standardized ethanolic GSE (200 m/kg/p.o.) for a period of 28 days resulted in significant reversal of above mentioned changes in the obese Wistar rats. CONCLUSION The present study has demonstrated the significant antiobesity potential of GSE in murine model of obesity.
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Affiliation(s)
- Vinay Kumar
- Department of Pharmacology, Faculty of Pharmacy, Hamdard University, New Delhi-110062, India
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