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1
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Shiozaki M, Kanno K, Yonezawa S, Otani Y, Shigenobu Y, Haratake D, Murakami E, Oka S, Ito M. Integrator complex subunit 6 promotes hepatocellular steatosis via β-catenin-PPARγ axis. Biochim Biophys Acta Mol Cell Biol Lipids 2024; 1869:159532. [PMID: 38981571 DOI: 10.1016/j.bbalip.2024.159532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 04/21/2024] [Accepted: 07/05/2024] [Indexed: 07/11/2024]
Abstract
Hepatic adipogenesis has common mechanisms with adipocyte differentiation such as PPARγ involvement and the induction of adipose tissue-specific molecules. A previous report demonstrated that integrator complex subunit 6 (INTS6) is required for adipocyte differentiation. This study aimed to investigate INTS6 expression and its role in hepatic steatosis progression. The expression of INTS6 and PPARγ was examined in the liver of a mouse model of steatohepatitis and in paired liver biopsy samples from 11 patients with severe obesity and histologically proven metabolic dysfunction associated steatohepatitis (MASH) before and one year after bariatric surgery. To induce hepatocellular steatosis in vitro, an immortalized human hepatocyte cell line Hc3716 was treated with free fatty acids. In the steatohepatitis mouse model, we observed hepatic induction of INTS6, PPARγ, and adipocyte-specific genes. In contrast, β-catenin which negatively regulates PPARγ was reduced. Biopsied human livers demonstrated a strong positive correlation (r2 = 0.8755) between INTS6 and PPARγ mRNA levels. After bariatric surgery, gene expressions of PPARγ, FABP4, and CD36 were mostly downregulated. In our in vitro experiments, we observed a concentration-dependent increase in Oil Red O staining in Hc3716 cells after treatment with the free fatty acids. Alongside this change, the expression of INTS6, PPARγ, and adipocyte-specific genes was induced. INTS6 knockdown using siRNA significantly suppressed cellular lipid accumulation together with induction of β-catenin and PPARγ downregulation. Collectively, INTS6 expression closely correlates with PPARγ. INTS6 suppression significantly reduced hepatocyte steatosis via β-catenin-PPARγ axis, indicating that INTS6 could be a novel therapeutic target for treating MASH.
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Affiliation(s)
- Minami Shiozaki
- Department of General Internal Medicine, Hiroshima University Hospital, Japan
| | - Keishi Kanno
- Department of General Internal Medicine, Hiroshima University Hospital, Japan.
| | - Sayaka Yonezawa
- Department of General Internal Medicine, Hiroshima University Hospital, Japan
| | - Yuichiro Otani
- Department of General Internal Medicine, Hiroshima University Hospital, Japan
| | - Yuya Shigenobu
- Department of General Internal Medicine, Hiroshima University Hospital, Japan
| | - Daisuke Haratake
- Department of General Internal Medicine, Hiroshima University Hospital, Japan
| | - Eisuke Murakami
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Japan
| | - Shiro Oka
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Japan
| | - Masanori Ito
- Department of General Internal Medicine, Hiroshima University Hospital, Japan
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Li X, Chen R, Kemper S, Brigstock DR. Production, Exacerbating Effect, and EV-Mediated Transcription of Hepatic CCN2 in NASH: Implications for Diagnosis and Therapy of NASH Fibrosis. Int J Mol Sci 2023; 24:12823. [PMID: 37629004 PMCID: PMC10454308 DOI: 10.3390/ijms241612823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 08/05/2023] [Accepted: 08/11/2023] [Indexed: 08/27/2023] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is characterized by steatosis, hepatocyte ballooning, and inflammation and may progress to include increasingly severe fibrosis, which portends more serious disease and is predictive of patient mortality. Diagnostic and therapeutic options for NASH fibrosis are limited, and the underlying fibrogenic pathways are under-explored. Cell communication network factor 2 (CCN2) is a well-characterized pro-fibrotic molecule, but its production in and contribution to NASH fibrosis requires further study. Hepatic CCN2 expression was significantly induced in NASH patients with F3-F4 fibrosis and was positively correlated with hepatic Col1A1, Col1A2, Col3A1, or αSMA expression. When wild-type (WT) or transgenic (TG) Swiss mice expressing enhanced green fluorescent protein (EGFP) under the control of the CCN2 promoter were fed up to 7 weeks with control or choline-deficient, amino-acid-defined diet with high (60%) fat (CDAA-HF), the resulting NASH-like hepatic pathology included a profound increase in CCN2 or EGFP immunoreactivity in activated hepatic stellate cells (HSC) and in fibroblasts and smooth muscle cells of the vasculature, with little or no induction of CCN2 in other liver cell types. In the context of CDAA-HF diet-induced NASH, Balb/c TG mice expressing human CCN2 under the control of the albumin promoter exhibited exacerbated deposition of interstitial hepatic collagen and activated HSC compared to WT mice. In vitro, palmitic acid-treated hepatocytes produced extracellular vesicles (EVs) that induced CCN2, Col1A1, and αSMA in HSC. Hepatic CCN2 may aid the assessment of NASH fibrosis severity and, together with pro-fibrogenic EVs, is a therapeutic target for reducing NASH fibrosis.
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Affiliation(s)
- Xinlei Li
- Center for Clinical and Translational Research, The Research Institute, Nationwide Children’s Hospital, Columbus, OH 43205, USA; (R.C.); (S.K.); (D.R.B.)
| | - Ruju Chen
- Center for Clinical and Translational Research, The Research Institute, Nationwide Children’s Hospital, Columbus, OH 43205, USA; (R.C.); (S.K.); (D.R.B.)
| | - Sherri Kemper
- Center for Clinical and Translational Research, The Research Institute, Nationwide Children’s Hospital, Columbus, OH 43205, USA; (R.C.); (S.K.); (D.R.B.)
| | - David R. Brigstock
- Center for Clinical and Translational Research, The Research Institute, Nationwide Children’s Hospital, Columbus, OH 43205, USA; (R.C.); (S.K.); (D.R.B.)
- Department of Surgery, Wexner Medical Center, The Ohio State University, Columbus, OH 43212, USA
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3
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Vachher M, Bansal S, Kumar B, Yadav S, Arora T, Wali NM, Burman A. Contribution of organokines in the development of NAFLD/NASH associated hepatocellular carcinoma. J Cell Biochem 2022; 123:1553-1584. [PMID: 35818831 DOI: 10.1002/jcb.30252] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 03/17/2022] [Accepted: 03/29/2022] [Indexed: 12/16/2022]
Abstract
Globally the incidence of hepatocellular carcinoma (HCC) is on an upsurge. Evidence is accumulating that liver disorders like nonalcoholic fatty liver disease (NAFLD) and its more progressive form nonalcoholic steatohepatitis (NASH) are associated with increased risk of developing HCC. NAFLD has a prevalence of about 25% and 50%-90% in obese population. With the growing burden of obesity epidemic worldwide, HCC presents a major healthcare burden. While cirrhosis is one of the major risk factors of HCC, available literature suggests that NAFLD/NASH associated HCC also develops in minimum or noncirrhotic livers. Therefore, there is an urgent need to understand the pathogenesis and risk factors associated with NAFLD and NASH related HCC that would help in early diagnosis and favorable prognosis of HCC secondary to NAFLD. Adipokines, hepatokines and myokines are factors secreted by adipocytes, hepatocytes and myocytes, respectively, playing essential roles in cellular homeostasis, energy balance and metabolism with autocrine, paracrine and endocrine effects. In this review, we endeavor to focus on the role of these organokines in the pathogenesis of NAFLD/NASH and its progression to HCC to augment the understanding of the factors stimulating hepatocytes to acquire a malignant phenotype. This shall aid in the development of novel therapeutic strategies and tools for early diagnosis of NAFLD/NASH and HCC.
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Affiliation(s)
- Meenakshi Vachher
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Savita Bansal
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Bhupender Kumar
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Sandeep Yadav
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Taruna Arora
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Nalini Moza Wali
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Archana Burman
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
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Cariou B, Byrne CD, Loomba R, Sanyal AJ. Nonalcoholic fatty liver disease as a metabolic disease in humans: A literature review. Diabetes Obes Metab 2021; 23:1069-1083. [PMID: 33464677 PMCID: PMC8248154 DOI: 10.1111/dom.14322] [Citation(s) in RCA: 126] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 01/14/2021] [Accepted: 01/14/2021] [Indexed: 02/06/2023]
Abstract
AIMS To conduct a systematic literature review to identify recent epidemiological, biomarker, genetic and clinical evidence that expands our understanding of nonalcoholic fatty liver disease (NAFLD) as a metabolic disorder. MATERIALS AND METHODS We performed a literature search using PubMed to identify trials, observational studies and meta-analyses published in the past 5 years. RESULTS A total of 95 publications met prespecified inclusion criteria and reported on the interplay between NAFLD/nonalcoholic steatohepatitis (NASH) and metabolic dysfunction, in terms of disease burden and/or epidemiology (n = 10), pathophysiology, risk factors and associated conditions (n = 29), diagnosis and biomarkers (n = 34), and treatment approaches (n = 22). There is a growing body of evidence on the links between NAFLD/NASH pathogenesis and mechanisms of metabolic dysfunction, through liver lipid accumulation, insulin resistance, inflammation, apoptosis, and fibrogenic remodelling within the liver. The frequent co-occurrence of NAFLD with obesity, metabolic syndrome and type 2 diabetes supports this premise. Therapeutic approaches originally envisaged for type 2 diabetes or obesity (such as glucagon-like peptide-1 receptor agonists, sodium-glucose co-transporter-2 inhibitors, insulin sensitizers and bariatric surgery) have shown promising signs of benefit for patients with NAFLD/NASH. CONCLUSIONS Given the complex interplay between NAFLD and metabolic dysfunction, there is an urgent need for multidisciplinary collaboration and established protocols for care of patients with NAFLD that are individualized and ideally support reduction of overall metabolic risk as well as treatment for NASH.
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Affiliation(s)
- Bertrand Cariou
- L'institut du Thorax, Department of EndocrinologyUNIV Nantes, Inserm, CNRS, CHU NantesNantesFrance
| | - Christopher D. Byrne
- Endocrinology and Metabolism, Human Development and Health, Faculty of MedicineUniversity of SouthamptonSouthamptonUK
- Southampton National Institute for Health Research, Biomedical Research Centre, University Hospital SouthamptonSouthamptonUK
| | - Rohit Loomba
- NAFLD Research Center, Division of GastroenterologyUniversity of California San DiegoSan DiegoCaliforniaUSA
| | - Arun J. Sanyal
- Department of Internal Medicine, Division of Gastroenterology, Hepatology and NutritionVirginia Commonwealth UniversityRichmondVirginiaUSA
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5
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Mavilia MG, Wu GY. Liver and serum adiponectin levels in non-alcoholic fatty liver disease. J Dig Dis 2021; 22:214-221. [PMID: 33675573 DOI: 10.1111/1751-2980.12980] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 02/13/2021] [Accepted: 03/03/2021] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Adiponectin is an adipokine that has anti-steatotic, anti-inflammatory and anti-fibrotic effects. The impact of these different activities impact on the development and progression of non-alcoholic fatty liver disease (NAFLD) is not well understood. The aim of this study was to evaluate both liver and serum adiponectin levels in patients with and without NAFLD and determine any clinical correlations. METHODS Liver tissue and serum samples were collected from patients undergoing liver biopsy between April 2014 and July 2020, and categorized based on histopathological diagnosis into hepatic steatosis (HS), non-alcoholic steatohepatitis (NASH), and hepatitis control (HC). A Luminex xMAP assay was performed on both liver and serum samples to measure adiponectin levels. Statistical analysis compared liver adiponectin (LA) and serum adiponectin (SA) levels between groups. RESULTS A total of 48 participants were included in the analysis. The mean LA level was lowest in the HS group, followed by the NASH group and the HC group (P = 0.036). The mean SA level was 3.61 μg/mL for the NAFLD group and was significantly lower than that in the HC (7.51 μg/mL; P = 0.001). CONCLUSION Adiponectin levels are lower in NAFLD compared to HC in both serum and liver tissue. LA levels in patients with HS were significantly lower than in both the NASH and HC groups, suggesting that adiponectin is related to inflammation in the liver and probably reflects its role in the pathogenesis of NAFLD.
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Affiliation(s)
- Marianna G Mavilia
- Department of Gastroenterology and Hepatology, University of Connecticut Health Center, Farmington, Connecticut, USA
| | - George Y Wu
- Department of Gastroenterology and Hepatology, University of Connecticut Health Center, Farmington, Connecticut, USA
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Kucukoglu O, Sowa JP, Mazzolini GD, Syn WK, Canbay A. Hepatokines and adipokines in NASH-related hepatocellular carcinoma. J Hepatol 2021; 74:442-457. [PMID: 33161047 DOI: 10.1016/j.jhep.2020.10.030] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 10/26/2020] [Accepted: 10/28/2020] [Indexed: 12/12/2022]
Abstract
The incidence of hepatocellular carcinoma (HCC) is increasing in industrialised societies; this is likely secondary to the increasing burden of non-alcoholic fatty liver disease (NAFLD), its progressive form non-alcoholic steatohepatitis (NASH), and the metabolic syndrome. Cumulative studies suggest that NAFLD-related HCC may also develop in non-cirrhotic livers. However, prognosis and survival do not differ between NAFLD- or virus-associated HCC. Thus, research has increasingly focused on NAFLD-related risk factors to better understand the biology of hepatocarcinogenesis and to develop new diagnostic, preventive, and therapeutic strategies. One important aspect thereof is the role of hepatokines and adipokines in NAFLD/NASH-related HCC. In this review, we compile current data supporting the use of hepatokines and adipokines as potential markers of disease progression in NAFLD or as early markers of NAFLD-related HCC. While much work must be done to elucidate the mechanisms and interactions underlying alterations to hepatokines and adipokines, current data support the possible utility of these factors - in particular, angiopoietin-like proteins, fibroblast growth factors, and apelin - for detection or even as therapeutic targets in NAFLD-related HCC.
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Affiliation(s)
- Ozlem Kucukoglu
- Department of Gastroenterology, Hepatology, and Infectious Diseases, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany
| | - Jan-Peter Sowa
- Department of Medicine, Ruhr University Bochum, University Hospital Knappschaftskrankenhaus Bochum, 44892 Bochum, Germany
| | - Guillermo Daniel Mazzolini
- Laboratory of Gene Therapy, Instituto de Investigaciones en Medicina Traslacional, CONICET-Universidad Austral, Buenos Aires 999071, Argentina; Liver Unit, Hospital Universitario Austral, Universidad Austral, Argentina
| | - Wing-Kin Syn
- Section of Gastroenterology, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, USA; Division of Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, SC, USA; Department of Physiology, Faculty of Medicine and Nursing, University of Basque Country UPV/EHU, 48940 Leioa, Vizcaya, Spain
| | - Ali Canbay
- Department of Gastroenterology, Hepatology, and Infectious Diseases, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany; Department of Medicine, Ruhr University Bochum, University Hospital Knappschaftskrankenhaus Bochum, 44892 Bochum, Germany.
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7
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Data on Adiponectin from 2010 to 2020: Therapeutic Target and Prognostic Factor for Liver Diseases? Int J Mol Sci 2020; 21:ijms21155242. [PMID: 32718097 PMCID: PMC7432057 DOI: 10.3390/ijms21155242] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 07/15/2020] [Accepted: 07/22/2020] [Indexed: 12/13/2022] Open
Abstract
The review describes the role of adiponectin in liver diseases in the presence and absence of surgery reported in the literature in the last ten years. The most updated therapeutic strategies based on the regulation of adiponectin including pharmacological and surgical interventions and adiponectin knockout rodents, as well as some of the scientific controversies in this field, are described. Whether adiponectin could be a potential therapeutic target for the treatment of liver diseases and patients submitted to hepatic resection or liver transplantation are discussed. Furthermore, preclinical and clinical data on the mechanism of action of adiponectin in different liver diseases (nonalcoholic fatty disease, alcoholic liver disease, nonalcoholic steatohepatitis, liver cirrhosis and hepatocellular carcinoma) in the absence or presence of surgery are evaluated in order to establish potential targets that might be useful for the treatment of liver disease as well as in the practice of liver surgery associated with the hepatic resections of tumors and liver transplantation.
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8
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Molecular Pathogenesis of Nonalcoholic Steatohepatitis- (NASH-) Related Hepatocellular Carcinoma. Can J Gastroenterol Hepatol 2018; 2018:8543763. [PMID: 30228976 PMCID: PMC6136489 DOI: 10.1155/2018/8543763] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 08/12/2018] [Indexed: 12/14/2022] Open
Abstract
The proportion of obese or diabetic population has been anticipated to increase in the upcoming decades, which rises the prevalence of nonalcoholic fatty liver disease (NAFLD) and its progression to nonalcoholic steatohepatitis (NASH). Recent evidence indicates that NASH is the main cause of chronic liver diseases and it is an important risk factor for development of hepatocellular carcinoma (HCC). Although the literature addressing NASH-HCC is growing rapidly, limited data is available about the etiology of NASH-related HCC. Experimental studies on the molecular mechanism of HCC development in NASH reveal that the carcinogenesis is relevant to complex changes in signaling pathways that mediate cell proliferation and energy metabolism. Genetic or epigenetic modifications and alterations in metabolic, immunologic, and endocrine pathways have been shown to be closely related to inflammation, liver injury, and fibrosis in NASH along with its subsequent progression to HCC. In this review, we provide an overview on the current knowledge of NASH-related HCC development and emphasize molecular signaling pathways regarding their mechanism of action in NASH-derived HCC.
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9
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Kobayashi H, Otsuka H, Yanai M, Hara M, Hishiki M, Soma M, Abe M. Adiponectin Receptor gene Polymorphisms are Associated with Kidney Function in Elderly Japanese Populations. J Atheroscler Thromb 2018; 26:328-339. [PMID: 30135333 PMCID: PMC6456456 DOI: 10.5551/jat.45609] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Aim: Adiponectin exhibits its biological effects through adiponectin receptors (AdipoR1 and AdipoR2), which are distributed in the kidneys, and activation of those receptors could prevent or ameliorate diabetic nephropathy. This study aimed to evaluate the associations between AdipoR single nucleotide polymorphisms (SNPs) and kidney function in an elderly Japanese population. Methods: A total of 271 elderly Japanese volunteers underwent anthropometric and laboratory tests (cystatin C-based eGFR and total and high molecular weight adiponectin levels at baseline and a follow-up visit). Genotype data were obtained for the selected 7 and 5 AdipoR1 and AdipoR2 SNPs, respectively. Results: In a cross-sectional analysis at baseline, we found a significant association between the AdipoR2 SNP rs12230440 and kidney function; eGFRcys tended to increase as the number of carriers of T alleles increased after adjustment for covariates and Bonferroni correction, although the association of the SNP and annual eGFR decline could not be identified in the longitudinal data. Regarding the variants rs16850797, rs11061925, and rs10773983, each of the allele G, allele C, and allele G showed nominally significant associations with higher eGFRcys. However, this failed to reach significance after Bonferroni correction. Conclusion: Here, an AdipoR2 SNP was associated with kidney function, suggesting that the effects of this polymorphism on adiponectin receptor may affect kidney function in the elderly Japanese population.
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Affiliation(s)
- Hiroki Kobayashi
- Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine
| | - Hiromasa Otsuka
- Division of General Medicine, Department of Internal Medicine, Nihon University School of Medicine
| | - Mitsuru Yanai
- Division of General Medicine, Department of Internal Medicine, Nihon University School of Medicine
| | - Motohiko Hara
- Department of Nursing, School of Health and Social Services, Saitama Prefectural University
| | - Mikano Hishiki
- Department of Diabetes and Endocrinology, Tokyo Metropolitan Hiroo Hospital
| | - Masayoshi Soma
- Division of General Medicine, Department of Internal Medicine, Nihon University School of Medicine
| | - Masanori Abe
- Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine
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10
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Borrelli A, Bonelli P, Tuccillo FM, Goldfine ID, Evans JL, Buonaguro FM, Mancini A. Role of gut microbiota and oxidative stress in the progression of non-alcoholic fatty liver disease to hepatocarcinoma: Current and innovative therapeutic approaches. Redox Biol 2018; 15:467-479. [PMID: 29413959 PMCID: PMC5975181 DOI: 10.1016/j.redox.2018.01.009] [Citation(s) in RCA: 187] [Impact Index Per Article: 26.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 01/10/2018] [Accepted: 01/17/2018] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) represents the most common chronic liver disease in industrialized countries. NAFLD progresses through the inflammatory phase of non-alcoholic steatohepatitis (NASH) to fibrosis and cirrhosis, with some cases developing liver failure or hepatocellular carcinoma (HCC). Liver biopsy remains the gold standard approach to a definitive diagnosis of NAFLD and the distinction between simple steatosis and NASH. The pathogenesis of NASH is still not clear. Several theories have been proposed ranging from the "Two Hit Theory" to the "Multiple Hit Theory". However, the general consensus is that the gut microbiota, oxidative stress, and mitochondrial damage play key roles in the pathogenesis of NASH. The interaction between the gut epithelia and some commensal bacteria induces the rapid generation of reactive oxygen species (ROS). The main goal of any therapy addressing NASH is to reverse or prevent progression to liver fibrosis/cirrhosis. This problem represents the first "Achilles' heel" of the new molecules being evaluated in most ongoing clinical trials. The second is the inability of these molecules to reach the mitochondria, the primary sites of energy production and ROS generation. Recently, a variety of non-pharmacological and pharmacological treatment approaches for NASH have been evaluated including vitamin E, the thiazolidinediones, and novel molecules related to NASH pathogenesis (including obeticholic acid and elafibranor). Recently, a new isoform of human manganese superoxide dismutase (MnSOD) was isolated and obtained in a synthetic recombinant form designated rMnSOD. This protein has been shown to be a powerful antioxidant capable of mediating ROS dismutation, penetrating biological barriers via its uncleaved leader peptide, and reducing portal hypertension and fibrosis in rats affected by liver cirrhosis. Based on these distinctive characteristics, it can be hypothesized that this novel recombinant protein (rMnSOD) potentially represents a new and highly efficient adjuvant therapy to counteract the progression from NASH to HCC.
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Affiliation(s)
- Antonella Borrelli
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS "Fondazione G Pascale", 80131 Napoli, Italy.
| | - Patrizia Bonelli
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS "Fondazione G Pascale", 80131 Napoli, Italy
| | - Franca Maria Tuccillo
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS "Fondazione G Pascale", 80131 Napoli, Italy
| | | | | | - Franco Maria Buonaguro
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS "Fondazione G Pascale", 80131 Napoli, Italy
| | - Aldo Mancini
- Leadhexa Biotechnologies Inc., Belvedere, CA, USA
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11
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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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12
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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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13
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Cimini FA, Barchetta I, Carotti S, Bertoccini L, Baroni MG, Vespasiani-Gentilucci U, Cavallo MG, Morini S. Relationship between adipose tissue dysfunction, vitamin D deficiency and the pathogenesis of non-alcoholic fatty liver disease. World J Gastroenterol 2017; 23:3407-3417. [PMID: 28596677 PMCID: PMC5442077 DOI: 10.3748/wjg.v23.i19.3407] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2016] [Revised: 02/28/2017] [Accepted: 04/13/2017] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. Its pathogenesis is complex and not yet fully understood. Over the years many studies have proposed various pathophysiological hypotheses, among which the currently most widely accepted is the “multiple parallel hits” theory. According to this model, lipid accumulation in the hepatocytes and insulin resistance increase the vulnerability of the liver to many factors that act in a coordinated and cooperative manner to promote hepatic injury, inflammation and fibrosis. Among these factors, adipose tissue dysfunction and subsequent chronic low grade inflammation play a crucial role. Recent studies have shown that vitamin D exerts an immune-regulating action on adipose tissue, and the growing wealth of epidemiological data is demonstrating that hypovitaminosis D is associated with both obesity and NAFLD. Furthermore, given the strong association between these conditions, current findings suggest that vitamin D may be involved in the relationship between adipose tissue dysfunction and NAFLD. The purpose of this review is to provide an overview of recent advances in the pathogenesis of NAFLD in relation to adipose tissue dysfunction, and in the pathophysiology linking vitamin D deficiency with NAFLD and adiposity, together with an overview of the evidence available on the clinical utility of vitamin D supplementation in cases of NAFLD.
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Stojsavljević S, Gomerčić Palčić M, Virović Jukić L, Smirčić Duvnjak L, Duvnjak M. Adipokines and proinflammatory cytokines, the key mediators in the pathogenesis of nonalcoholic fatty liver disease. World J Gastroenterol 2014; 20:18070-18091. [PMID: 25561778 PMCID: PMC4277948 DOI: 10.3748/wjg.v20.i48.18070] [Citation(s) in RCA: 247] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2014] [Revised: 10/21/2014] [Accepted: 11/18/2014] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a condition in which excess fat accumulates in the liver of a patient with no history of alcohol abuse or other causes for secondary hepatic steatosis. The pathogenesis of NAFLD and nonalcoholic steatohepatitis (NASH) has not been fully elucidated. The "two-hit" hypothesis is probably a too simplified model to elaborate complex pathogenetic events occurring in patients with NASH. It should be better regarded as a multiple step process, with accumulation of liver fat being the first step, followed by the development of necroinflammation and fibrosis. Adipose tissue, which has emerged as an endocrine organ with a key role in energy homeostasis, is responsive to both central and peripheral metabolic signals and is itself capable of secreting a number of proteins. These adipocyte-specific or enriched proteins, termed adipokines, have been shown to have a variety of local, peripheral, and central effects. In the current review, we explore the role of adipocytokines and proinflammatory cytokines in the pathogenesis of NAFLD. We particularly focus on adiponectin, leptin and ghrelin, with a brief mention of resistin, visfatin and retinol-binding protein 4 among adipokines, and tumor necrosis factor-α, interleukin (IL)-6, IL-1, and briefly IL-18 among proinflammatory cytokines. We update their role in NAFLD, as elucidated in experimental models and clinical practice.
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Nonalcoholic Fatty liver disease: pathogenesis and therapeutics from a mitochondria-centric perspective. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2014; 2014:637027. [PMID: 25371775 PMCID: PMC4211163 DOI: 10.1155/2014/637027] [Citation(s) in RCA: 107] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Revised: 07/31/2014] [Accepted: 07/31/2014] [Indexed: 12/12/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) describes a spectrum of disorders characterized by the accumulation of triglycerides within the liver. The global prevalence of NAFLD has been increasing as the obesity epidemic shows no sign of relenting. Mitochondria play a central role in hepatic lipid metabolism and also are affected by upstream signaling pathways involved in hepatic metabolism. This review will focus on the role of mitochondria in the pathophysiology of NAFLD and touch on some of the therapeutic approaches targeting mitochondria as well as metabolically important signaling pathways. Mitochondria are able to adapt to lipid accumulation in hepatocytes by increasing rates of beta-oxidation; however increased substrate delivery to the mitochondrial electron transport chain (ETC) leads to increased reactive oxygen species (ROS) production and eventually ETC dysfunction. Decreased ETC function combined with increased rates of fatty acid beta-oxidation leads to the accumulation of incomplete products of beta-oxidation, which combined with increased levels of ROS contribute to insulin resistance. Several related signaling pathways, nuclear receptors, and transcription factors also regulate hepatic lipid metabolism, many of which are redox sensitive and regulated by ROS.
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Takaki A, Kawai D, Yamamoto K. Molecular mechanisms and new treatment strategies for non-alcoholic steatohepatitis (NASH). Int J Mol Sci 2014; 15:7352-79. [PMID: 24786095 PMCID: PMC4057677 DOI: 10.3390/ijms15057352] [Citation(s) in RCA: 90] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2014] [Revised: 03/28/2014] [Accepted: 04/10/2014] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease (NAFLD), in which most patients exhibit non-progressive, non-alcoholic fatty liver (NAFL) attributable to simple steatosis. Multiple hits, including genetic differences, fat accumulation, insulin resistance and intestinal microbiota changes, account for the progression of NASH. NAFLD is strongly associated with obesity, which induces adipokine secretion, endoplasmic reticulum (ER) and oxidative stress at the cellular level, which in turn induces hepatic steatosis, inflammation and fibrosis. Among these factors, gut microbiota are acknowledged as having an important role in initiating this multifactorial disease. Oxidative stress is considered to be a key contributor in the progression from NAFL to NASH. Macrophage infiltration is apparent in NAFL and NASH, while T-cell infiltration is apparent in NASH. Although several clinical trials have shown that antioxidative therapy with vitamin E can effectively control hepatitis pathology in the short term, the long-term effects remain obscure and have often proved to be ineffective in many other diseases. Several long-term antioxidant protocols have failed to reduce mortality. New treatment modalities that incorporate current understanding of NAFLD molecular pathogenesis must be considered.
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Affiliation(s)
- Akinobu Takaki
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.
| | - Daisuke Kawai
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.
| | - Kazuhide Yamamoto
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.
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Takaki A, Kawai D, Yamamoto K. Multiple hits, including oxidative stress, as pathogenesis and treatment target in non-alcoholic steatohepatitis (NASH). Int J Mol Sci 2013; 14:20704-28. [PMID: 24132155 PMCID: PMC3821639 DOI: 10.3390/ijms141020704] [Citation(s) in RCA: 320] [Impact Index Per Article: 26.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2013] [Revised: 09/18/2013] [Accepted: 09/29/2013] [Indexed: 12/12/2022] Open
Abstract
Multiple parallel hits, including genetic differences, insulin resistance and intestinal microbiota, account for the progression of non-alcoholic steatohepatitis (NASH). Multiple hits induce adipokine secretion, endoplasmic reticulum (ER) and oxidative stress at the cellular level that subsequently induce hepatic steatosis, inflammation and fibrosis, among which oxidative stress is considered a key contributor to progression from simple fatty liver to NASH. Although several clinical trials have shown that anti-oxidative therapy can effectively control hepatitis activities in the short term, the long-term effect remains obscure. Several trials of long-term anti-oxidant protocols aimed at treating cerebrovascular diseases or cancer development have failed to produce a benefit. This might be explained by the non-selective anti-oxidative properties of these drugs. Molecular hydrogen is an effective antioxidant that reduces only cytotoxic reactive oxygen species (ROS) and several diseases associated with oxidative stress are sensitive to hydrogen. The progress of NASH to hepatocellular carcinoma can be controlled using hydrogen-rich water. Thus, targeting mitochondrial oxidative stress might be a good candidate for NASH treatment. Long term clinical intervention is needed to control this complex lifestyle-related disease.
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Affiliation(s)
- Akinobu Takaki
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama City, Okayama 700-8558, Japan.
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Carulli L, Ballestri S, Lonardo A, Lami F, Violi E, Losi L, Bonilauri L, Verrone AM, Odoardi MR, Scaglioni F, Bertolotti M, Loria P. Is nonalcoholic steatohepatitis associated with a high-though-normal thyroid stimulating hormone level and lower cholesterol levels? Intern Emerg Med 2013; 8:297-305. [PMID: 21559749 DOI: 10.1007/s11739-011-0609-4] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2010] [Accepted: 04/21/2011] [Indexed: 02/06/2023]
Abstract
Hypothyroidism is associated with the risk of development of the metabolic syndrome (MS) and hypercholesterolemia. Direct evidence that hypothyroidism might be associated with advanced chronic liver disease via nonalcoholic steatohepatitis (NASH) is limited. We studied the relationship between thyroid hormones, thyroid stimulating hormone (TSH), cholesterol, and NASH. In consecutive euthyroid patients with biopsy-proven nonalcoholic fatty liver disease, TSH and thyroid hormone (FT3 and FT4) concentrations were compared in 25 patients with steatosis and 44 non-cirrhotic NASH patients featuring concurrent ballooning, lobular inflammation and steatosis. The MS was diagnosed according to ATP III criteria. A meta-analysis of previously published studies was performed to evaluate whether NASH, compared to simple steatosis, is associated with lower cholesterol levels. At univariate analysis, compared to those with steatosis, patients with NASH have a wider waist, elevated levels of BMI, ALT, AST, fasting insulin, HOMA-IR, ferritin, TSH and a lower serum cholesterol. At stepwise multivariable logistic regression analysis, the independent predictors of NASH are high HOMA and TSH and lower total cholesterol (Model 1); MS and high TSH (Model 2). At meta-analysis, serum total cholesterol levels are significantly lower in predominantly non-cirrhotic NASH than in simple steatosis. This study provides cross-sectional and meta-analytic evidence that, in euthyroid patients, high-though-normal TSH values are independently associated with NASH. Further work is needed to ascertain the role, if any, of lower cholesterol serum levels in assisting in the diagnosis of NASH.
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Affiliation(s)
- Lucia Carulli
- Department of Internal Medicine, Endocrinology, Metabolism and Geriatrics, Unit of Internal Medicine, University of Modena and Reggio Emilia, Nuovo Ospedale Civile Sant'Agostino Estense, Via Giardini 1355, 41100, Modena, Italy
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Finelli C, Tarantino G. What is the role of adiponectin in obesity related non-alcoholic fatty liver disease? World J Gastroenterol 2013; 19:802-812. [PMID: 23430039 PMCID: PMC3574877 DOI: 10.3748/wjg.v19.i6.802] [Citation(s) in RCA: 134] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2012] [Revised: 12/03/2012] [Accepted: 12/15/2012] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is recognized as the most common type of chronic liver disease in Western countries. Insulin resistance is a key factor in the pathogenesis of NAFLD, the latter being considered as the hepatic component of insulin resistance or obesity. Adiponectin is the most abundant adipose-specific adipokine. There is evidence that adiponectin decreases hepatic and systematic insulin resistance, and attenuates liver inflammation and fibrosis. Adiponectin generally predicts steatosis grade and the severity of NAFLD; however, to what extent this is a direct effect or related to the presence of more severe insulin resistance or obesity remains to be addressed. Although there is no proven pharmacotherapy for the treatment of NAFLD, recent therapeutic strategies have focused on the indirect upregulation of adiponectin through the administration of various therapeutic agents and/or lifestyle modifications. In this adiponectin-focused review, the pathogenetic role and the potential therapeutic benefits of adiponectin in NAFLD are analyzed systematically.
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Chen MJ, Yeh YT, Lee KT, Tsai CJ, Lee HH, Wang SN. The promoting effect of adiponectin in hepatocellular carcinoma. J Surg Oncol 2012; 106:181-7. [PMID: 22287480 DOI: 10.1002/jso.23059] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2011] [Accepted: 01/09/2012] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND OBJECTIVES Adipokines may explain the newly established association of obesity with hepatocellular carcinoma (HCC). This study investigated if adiponectin levels in HCC patients differed from healthy controls and their potential effect in the development of HCC. METHODS Radioimmunoassay was used to determine serum adiponectin levels of 65 HCC patients and 165 healthy controls. The expressions of adiponectin protein in the tumor and adjacent non-tumor parts were examined by the immunoblotting method. Cell proliferation assays were used to assess the bioeffects of adiponectin in two human liver cancer cell lines. RESULTS Serum adiponectin levels were significantly higher in the HCC patients than the controls. Significant correlations of serum adiponectin levels with serum triglyceride levels and insulin resistance were found in the controls, but not in the HCC patients. In contrast, serum adiponectin levels significantly correlated with serum albumin and alkaline phosphatase levels in the HCC patients, but this trend was not observed in the controls. The expression pattern of adiponectin protein between the paired tumor and adjacent non-tumor tissues significantly correlated with tumor size. In vitro, adiponectin increased cell proliferation in a dose-dependent manner. CONCLUSIONS Increased adiponectin expressions were found in HCC and this increase might contribute to tumor growth.
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Affiliation(s)
- Ming-Jenn Chen
- Division of General Surgery, Department of Surgery, Chi Mei Medical Center, Tainan, Taiwan, R.O.C
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Shafiei MS, Shetty S, Scherer PE, Rockey DC. Adiponectin regulation of stellate cell activation via PPARγ-dependent and -independent mechanisms. THE AMERICAN JOURNAL OF PATHOLOGY 2011; 178:2690-9. [PMID: 21641391 DOI: 10.1016/j.ajpath.2011.02.035] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 09/19/2010] [Revised: 01/24/2011] [Accepted: 02/10/2011] [Indexed: 12/11/2022]
Abstract
In this study, we elucidated the mechanism by which adiponectin modulates hepatic stellate cell activation and fibrogenesis. Adiponectin-overexpressing transgenic mice receiving thioacetamide were resistant to fibrosis, compared with controls. In contrast, adiponectin-null animals developed severe fibrosis. Expression of collagen α1(I) and α-smooth muscle actin (α-SMA) mRNAs were significantly lower in adiponectin-overexpressing mice, compared with controls. In wild-type stellate cells exposed to a lentivirus encoding adiponectin, expression of peroxisome proliferator-activated receptor-γ (PPARγ), SREBP1c, and CEBPα mRNAs was significantly increased (3.2-, 4.1-, and 2.2-fold, respectively; n = 3; P < 0.05, adiponectin virus versus control), consistent with possible activation of an adipogenic transcriptional program. Troglitazone, a PPARγ agonist, strongly suppressed up-regulation of collagen α1(I) and α-SMA mRNA in stellate cells isolated from wild-type mice; however, stellate cells from adiponectin-null animals failed to respond to troglitazone. Furthermore, in isolated stellate cells in which PPARγ was depleted using an adenovirus-Cre-recombinase system and in which adiponectin was also overexpressed, collagen α1(I) and α-SMA were significantly inhibited. We conclude that the PPARγ effect on stellate cell activation and the fibrogenic cascade appears to be adiponectin-dependent; however, the inhibitory effect of adiponectin on stellate cell activation was not dependent on PPARγ, suggesting the presence of PPARγ-dependent as well as independent pathways in stellate cells.
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Affiliation(s)
- Mahnoush S Shafiei
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
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Siitonen N, Pulkkinen L, Lindström J, Kolehmainen M, Schwab U, Eriksson JG, Ilanne-Parikka P, Keinänen-Kiukaanniemi S, Tuomilehto J, Uusitupa M. Association of ADIPOR2 gene variants with cardiovascular disease and type 2 diabetes risk in individuals with impaired glucose tolerance: the Finnish Diabetes Prevention Study. Cardiovasc Diabetol 2011; 10:83. [PMID: 21943112 PMCID: PMC3196906 DOI: 10.1186/1475-2840-10-83] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2011] [Accepted: 09/24/2011] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Adiponectin is an adipokine with insulin-sensitising and anti-atherogenic effects. Two receptors for adiponectin, ADIPOR1 and ADIPOR2, have been characterized that mediate effects of adiponectin in various tissues. We examined whether genetic variation in ADIPOR2 predicts the development of cardiovascular disease (CVD) and/or Type 2 Diabetes (T2DM) in individuals with impaired glucose tolerance (IGT) participating the Finnish Diabetes Prevention Study (DPS). METHODS CVD morbidity and mortality data were collected during a median follow-up of 10.2 years (range 1-13 years) and conversion from IGT to T2DM was assessed during a median follow-up of 7 years (range 1-11 years). Altogether eight SNPs in the ADIPOR2 locus were genotyped in 484 participants of the DPS. Moreover, the same SNPs were genotyped and the mRNA expression levels of ADIPOR2 were determined in peripheral blood mononuclear cells and subcutaneous adipose tissue samples derived from 56 individuals participating in the Genobin study. RESULTS In the DPS population, four SNPs (rs10848554, rs11061937, rs1058322, rs16928751) were associated with CVD risk, and two remained significant (p = 0.014 for rs11061937 and p = 0.020 for rs1058322) when all four were included in the same multi-SNP model. Furthermore, the individuals homozygous for the rare minor alleles of rs11061946 and rs11061973 had increased risk of converting from IGT to T2DM. Allele-specific differences in the mRNA expression levels for the rs1058322 variant were seen in peripheral blood mononuclear cells derived from participants of the Genobin study. CONCLUSIONS Our results suggest that SNPs in the ADIPOR2 may modify the risk of CVD in individuals with IGT, possibly through alterations in the mRNA expression levels. In addition an independent genetic signal in ADIPOR2 locus may have an impact on the risk of developing T2DM in individuals with IGT. TRIAL REGISTRATION NUMBER ClinicalTrials.gov NCT00518167.
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Affiliation(s)
- Niina Siitonen
- Department of Clinical Nutrition and Food and Health Research Centre, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Leena Pulkkinen
- Department of Clinical Nutrition and Food and Health Research Centre, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Jaana Lindström
- Department of Health Promotion and Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland
- Department of Public Health, University of Helsinki, Helsinki, Finland
| | - Marjukka Kolehmainen
- Department of Clinical Nutrition and Food and Health Research Centre, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Ursula Schwab
- Department of Clinical Nutrition and Food and Health Research Centre, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
- Institute of Medicine, Clinical Medicine, Kuopio University Hospital, Kuopio, Finland
| | - Johan G Eriksson
- Department of Health Promotion and Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland
- Folkhalsan Research Centre, Helsinki, Finland
- Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland
- Vasa Central Hospital, Vasa, Finland
- Unit of General Practice, Helsinki University Central Hospital, Helsinki, Finland
| | - Pirjo Ilanne-Parikka
- Diabetes Centre, Finnish Diabetes Association, Tampere, Finland
- Science Centre, Pirkanmaa Hospital District, Tampere University Hospital, Tampere, Finland
| | - Sirkka Keinänen-Kiukaanniemi
- Institute of Health Sciences, University of Oulu, Oulu, Finland
- Unit of General Practice, Oulu University Hospital, Oulu, Finland
- Health Centre of Oulu, Oulu Finland
| | - Jaakko Tuomilehto
- Department of Health Promotion and Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland
- Department of Public Health, University of Helsinki, Helsinki, Finland
- South Ostrobothnia Central Hospital, Seinäjoki, Finland
- Department of Preventive and Clinical Medicine, Danube-Universität Krems, Krems, Austria
| | - Matti Uusitupa
- Department of Clinical Nutrition and Food and Health Research Centre, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
- Research Unit, Kuopio University Hospital, Kuopio, Finland
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Walter R, Wanninger J, Bauer S, Eisinger K, Neumeier M, Weiss TS, Amann T, Hellerbrand C, Schäffler A, Schölmerich J, Buechler C. Adiponectin reduces connective tissue growth factor in human hepatocytes which is already induced in non-fibrotic non-alcoholic steatohepatitis. Exp Mol Pathol 2011; 91:740-4. [PMID: 21946149 DOI: 10.1016/j.yexmp.2011.09.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2011] [Accepted: 09/04/2011] [Indexed: 12/16/2022]
Abstract
Connective tissue growth factor (CTGF) is induced in liver fibrosis and enhances the activity of transforming growth factor β (TGFβ). Recently we have shown that the hepatoprotective adipokine adiponectin downregulates CTGF in primary human hepatocytes (PHH). In the current study, the mechanisms mediating suppression of CTGF by adiponectin and the well described downstream effector of adiponectin receptor 2 (AdipoR2), peroxisome proliferator activated receptor α (PPARα), were analyzed in more detail. Adiponectin downregulated CTGF mRNA and protein in primary human hepatocytes (PHH) and suppression was blocked by a PPARα antagonist indicating that AdipoR2 is involved. The PPARα agonists fenofibrate and WY14643 also reduced CTGF protein in these cells. Adiponectin further impaired TGFβ-mediated upregulation of CTGF. Phosphorylation of the TGFβ downstream effectors SMAD2 and -3 was reduced in PHH incubated with adiponectin or PPARα agonists suggesting that early steps in TGFβ signal transduction are impaired. CTGF and TGFβ mRNA levels were increased in human non-fibrotic non-alcoholic steatohepatitis (NASH), and here AdipoR2 expression was significantly reduced. Current data show that CTGF and TGFβ are already induced in non-fibrotic NASH and this may be partly explained by low adiponectin bioactivity which interferes with TGFβ signaling by reducing phosphorylation of SMAD2/3 and by downregulating CTGF.
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Affiliation(s)
- Roland Walter
- Department of Internal Medicine I, University Hospital of Regensburg, Germany
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25
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Corbetta S, Redaelli A, Pozzi M, Bovo G, Ratti L, Redaelli E, Pellegrini C, Beck-Peccoz P, Spada A. Fibrosis is associated with adiponectin resistance in chronic hepatitis C virus infection. Eur J Clin Invest 2011; 41:898-905. [PMID: 21539538 DOI: 10.1111/j.1365-2362.2011.02498.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Chronic hepatitis C virus (HCV) infection is frequently associated with insulin resistance which has been suggested to promote fibrotic progression. Adiponectin, an adipocyte-derived insulin-sensitizing hormone, might play a protective role against hepatic fibrosis. MATERIALS AND METHODS This observational case-control study investigated the adiponectin status in insulin resistant, nondiabetic, chronic HCV-infected patients (n=54; 13 women, 41 men) compared with age-, sex- and BMI-matched healthy controls. Liver biopsies from patients with chronic HCV hepatitis were analysed for the adiponectin and adiponectin receptors (ADIPOR) 1 and 2 mRNA and protein expressions. RESULTS Serum adiponectin levels were higher in patients with chronic HCV hepatitis than in healthy controls (12·1±4·7 vs. 9·5±4·4 mg L(-1) in men, P = 0·01; 18·2±4·4 vs. 13·6±5·3mgL(-1) in women, P=0·02). BMI, HDL cholesterol and triglycerides levels correlated with adiponectin levels both in patients and in controls, while no correlation with glucose, insulin and HOMA-IR values could be detected. Nonetheless, insulin resistance was predictive of steatosis and fibrosis in chronic HCV-infected patients. Interestingly, patients with none or mild fibrosis showed serum adiponectin levels similar to those in healthy controls, while hyperadiponectinemia was associated with moderate to severe stages of fibrosis. Hyperadiponectinemia was unlikely sustained by liver production as hepatocytes did not express the protein. ADIPOR1 mRNA, but not ADIPOR2 levels, was reduced in chronic HCV hepatitis. The reduced ADIPOR1 expression was confirmed by immunohistochemistry. CONCLUSIONS In patients with chronic HCV hepatitis, fibrosis was associated with hyperadiponectinemia. Chronic HCV-infected hepatocytes showed reduced ADIPOR1 expression, suggesting a pattern of adiponectin resistance.
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Affiliation(s)
- Sabrina Corbetta
- Endocrinology and Diabetology Unit, Department of Medical-Surgical Sciences, University of Milan, Milan, Italy.
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Impact of artificial sunlight therapy on the progress of non-alcoholic fatty liver disease in rats. J Hepatol 2011; 55:415-25. [PMID: 21184788 DOI: 10.1016/j.jhep.2010.11.028] [Citation(s) in RCA: 116] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2009] [Revised: 10/31/2010] [Accepted: 11/22/2010] [Indexed: 01/10/2023]
Abstract
BACKGROUND & AIMS Non-alcoholic steatohepatitis (NASH) is recognized as the most severe form of non-alcoholic fatty liver disease, with likely progression to liver cirrhosis and hepatocellular carcinoma. However, there is no unified standard for diagnosis and therapeutics. This study aimed to characterize lipid transfer/metabolic proteins as non-invasive diagnostic markers, and to evaluate the therapeutic effects of phototherapy on the progression of NASH in rats. METHODS Lewis rats given a choline-deficient and iron-supplemented l-amino acid-defined (CDAA) diet and Zucker fa/fa rats were used as a diet-induced and an obesity-related NASH models, respectively, with or without phototherapy. RESULTS Serum apolipoprotein E and low molecular weight-adiponectin levels were gradually reduced and reached the lowest level at fatty liver/NASH stage both in CDAA diet-induced NASH model and in genetically obese model. Total-adiponectin levels were dramatically elevated after NASH was established in CDAA diet-induced NASH model. Phototherapy ameliorated hepatocyte apoptosis, inflammation, fibrosis, and insulin/leptin resistance caused by CDAA diet with alteration of the levels of lipid transfer/metabolic proteins and elevation of the circulating active form of vitamin D(3). Vitamin D(3) supplementation ameliorated NASH progression in CDAA diet-induced NASH model. However, phototherapy failed to ameliorate the obesity and steatosis, suggesting that phototherapy may possess anti-inflammatory/fibrotic activity rather than anti-obesity/steatotic activity. CONCLUSIONS These results suggest that serum lipid transfer/metabolic proteins and vitamin D(3) status may be effective biomarkers for non-invasive diagnosis of NASH progression, and that phototherapy may be a good complementary therapy for NASH because of its regulation of lipid transfer/metabolic proteins and vitamin D(3).
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Carazo A, León J, Casado J, Gila A, Delgado S, Martín A, Sanjuan L, Caballero T, Muñoz JA, Quiles R, Ruiz-Extremera A, Alcázar LM, Salmerón J. Hepatic expression of adiponectin receptors increases with non-alcoholic fatty liver disease progression in morbid obesity in correlation with glutathione peroxidase 1. Obes Surg 2011; 21:492-500. [PMID: 21240660 DOI: 10.1007/s11695-010-0353-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND The prevalence of non-alcoholic fatty liver disease (NAFLD) in obesity is very high. The role of adiponectin receptors in NAFLD progression remains still unclear. We speculate that changes in the hepatic expression levels of the two adiponectin receptors may be associated with the expression of oxidative stress-related genes. METHODS We studied 60 morbidly obese patients with NAFLD, who underwent liver biopsy at the time of bariatric surgery. We measured the hepatic messenger-RNA concentration of adiponectin receptors (ADIPOR1 and ADIPOR2), glutathione peroxidase 1 (GPx1), glutathione reductase (GRd) and inducible oxide nitric synthase. Additionally, biochemical parameters and oxidative stress markers were determined in blood samples. According to the Kleiner score, the patients were divided into two groups: group 1 (25 patients without steatohepatitis) and group 2 (25 patients with probable steatohepatitis and ten patients with steatohepatitis). RESULTS The messenger-RNA concentration of all genes analysed in the study was higher among the patients in group 2. However, no differences in blood oxidative stress markers were observed. Strong correlations were found among the expression levels of ADIPOR1, ADIPOR2 and GPx1. The multivariate analysis showed that the only independent variable associated with NAFLD progression was the increase in GPx1 expression levels. CONCLUSIONS NAFLD progression in morbid obesity is associated with increase in hepatic adiponectin receptor and oxidative stress-related genes. The linear correlations suggest that ADIPOR1, ADIPOR2 and GPx1 share key molecular factors in the regulation of the genetic expressions.
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Affiliation(s)
- Angel Carazo
- Research Unit, San Cecilio University Hospital, Av de Madrid s/n, 18012, Granada, Spain.
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Buechler C, Wanninger J, Neumeier M. Adiponectin, a key adipokine in obesity related liver diseases. World J Gastroenterol 2011; 17:2801-11. [PMID: 21734787 PMCID: PMC3120939 DOI: 10.3748/wjg.v17.i23.2801] [Citation(s) in RCA: 104] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2010] [Revised: 11/17/2010] [Accepted: 11/24/2010] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) comprising hepatic steatosis, non-alcoholic steatohepatitis (NASH), and progressive liver fibrosis is considered the most common liver disease in western countries. Fatty liver is more prevalent in overweight than normal-weight people and liver fat positively correlates with hepatic insulin resistance. Hepatic steatosis is regarded as a benign stage of NAFLD but may progress to NASH in a subgroup of patients. Besides liver biopsy no diagnostic tools to identify patients with NASH are available, and no effective treatment has been established. Visceral obesity is a main risk factor for NAFLD and inappropriate storage of triglycerides in adipocytes and higher concentrations of free fatty acids may add to increased hepatic lipid storage, insulin resistance, and progressive liver damage. Most of the adipose tissue-derived proteins are elevated in obesity and may contribute to systemic inflammation and liver damage. Adiponectin is highly abundant in human serum but its levels are reduced in obesity and are even lower in patients with hepatic steatosis or NASH. Adiponectin antagonizes excess lipid storage in the liver and protects from inflammation and fibrosis. This review aims to give a short survey on NAFLD and the hepatoprotective effects of adiponectin.
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Polyzos SA, Toulis KA, Goulis DG, Zavos C, Kountouras J. Serum total adiponectin in nonalcoholic fatty liver disease: a systematic review and meta-analysis. Metabolism 2011; 60:313-26. [PMID: 21040935 DOI: 10.1016/j.metabol.2010.09.003] [Citation(s) in RCA: 242] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2010] [Revised: 08/30/2010] [Accepted: 09/14/2010] [Indexed: 02/07/2023]
Abstract
Hypoadiponectinemia might represent a risk factor for nonalcoholic fatty liver disease (NAFLD). We performed a systematic review and meta-analysis to evaluate the serum total adiponectin levels in patients with simple nonalcoholic fatty liver (NAFL), those with nonalcoholic steatohepatitis (NASH), and controls. Data were extracted from PubMed, EMBASE, and Cochrane Central Register of Controlled Trials electronic databases (up to December 2009). The main outcome was the weighted mean differences (WMDs) in adiponectin between comparison groups. Twenty-eight studies were included in the systematic review. A meta-analysis of 27 studies that reported data on 2243 subjects (698 controls and 1545 patients with NAFLD) was performed. Controls had higher serum adiponectin compared with NAFL patients (12 studies, random-effects WMD [95% confidence interval {CI}] = 3.00 [1.57-4.43], I² = 80.4%) or NASH patients (19 studies, random-effects WMD [95% CI] = 4.75 [3.71-5.78], I² = 84.1%). The NASH patients demonstrated lower adiponectin compared with NAFL patients (19 studies, random-effects WMD [95% CI] = 1.81 [1.09-2.53], I² = 71.7%). By performing a meta-regression analysis, body mass index, age, sex, and type 2 diabetes mellitus failed to account for heterogeneity. However, the performance of liver biopsy on controls had significant effect on the outcome and accounted for 76.7%, 85.5%, and 22.8% of the between-study variance for comparisons between controls vs NAFLD, NAFL, and NASH patients, respectively. Based on liver histology, serum adiponectin levels are similar in NAFL patients and controls, but hypoadiponectinemia may play an important pathophysiological role in the progression from NAFL to NASH.
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Affiliation(s)
- Stergios A Polyzos
- Second Medical Clinic, Medical School, Aristotle University of Thessaloniki, Ippokration Hospital, 54642 Thessaloniki, Greece.
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Liu S, Wu HJ, Zhang ZQ, Chen Q, Liu B, Wu JP, Zhu L. The ameliorating effect of rosiglitazone on experimental nonalcoholic steatohepatitis is associated with regulating adiponectin receptor expression in rats. Eur J Pharmacol 2011; 650:384-9. [DOI: 10.1016/j.ejphar.2010.09.082] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2010] [Revised: 09/14/2010] [Accepted: 09/20/2010] [Indexed: 10/18/2022]
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Wanninger J, Neumeier M, Hellerbrand C, Schacherer D, Bauer S, Weiss TS, Huber H, Schäffler A, Aslanidis C, Schölmerich J, Buechler C. Lipid accumulation impairs adiponectin-mediated induction of activin A by increasing TGFbeta in primary human hepatocytes. Biochim Biophys Acta Mol Cell Biol Lipids 2010; 1811:626-33. [PMID: 21070865 DOI: 10.1016/j.bbalip.2010.11.001] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2010] [Revised: 10/20/2010] [Accepted: 11/02/2010] [Indexed: 12/18/2022]
Abstract
Fatty liver is commonly detected in obesity and has been identified as a risk factor for the progression of hepatic fibrosis in a wide range of liver diseases. Transforming growth factor beta (TGFβ) and activin A, both members of the TGFβ superfamiliy, are central regulators in liver fibrosis and regeneration, and the effect of hepatocyte lipid accumulation on the release of these proteins was studied. Primary human hepatocytes (PHH) were incubated with palmitic acid or oleic acid to increase lipid storage. Whereas activin A and its natural inhibitor follistatin were not affected, TGFβ was 2-fold increased. The hepatoprotective adipokine adiponectin dose-dependently induced activin A while lowering follistatin but did not alter TGFβ. Activin A was markedly reduced in hepatocyte cell lines compared to PHH and was not induced upon adiponectin incubation demonstrating significant differences of primary and transformed cells. In free fatty acid (FFA)-incubated PHH adiponectin-mediated induction of activin A was impaired. Inhibition of TGFβ receptors ALK4/5 and blockage of SMAD3 phosphorylation rescued activin A synthesis in FFA and in TGFβ incubated cells suggesting that FFA inhibit adiponectin activity by inducing TGFβ. To evaluate whether serum levels of activin A and its antagonist are altered in patients with hepatic steatosis, both proteins were measured in the serum of patients with sonographically diagnosed fatty liver and age- and BMI-matched controls. Systemic adiponectin was significantly reduced in patients with fatty liver but activin A and follistatin were not altered. In summary the current data demonstrate that lipid accumulation in hepatocytes induces TGFβ which impairs adiponectin bioactivity, and thereby may contribute to liver injury.
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Affiliation(s)
- Josef Wanninger
- Department of Internal Medicine I, University of Regensburg, Regensburg, Germany
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Kursawe R, Narayan D, Cali AM, Shaw M, Pierpont B, Shulman GI, Caprio S. Downregulation of ADIPOQ and PPARγ2 gene expression in subcutaneous adipose tissue of obese adolescents with hepatic steatosis. Obesity (Silver Spring) 2010; 18:1911-7. [PMID: 20168312 PMCID: PMC3898705 DOI: 10.1038/oby.2010.23] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Hepatic steatosis is associated with hypoadiponectinemia. The mechanism(s) resulting in lower serum adiponectin levels in obese adolescents with fatty liver is unknown. In two groups of equally obese adolescents, but discordant for hepatic fat content, we measured adiponectin, leptin, peroxisome proliferator-activated receptor γ 2 (PPARγ2) and tumor necrosis factor-α (TNFα) gene expression in the abdominal subcutaneous adipose tissue (SAT). Twenty six adolescents with similar degrees of obesity underwent a subcutaneous periumbilical adipose tissue biopsy, in addition to metabolic (oral glucose tolerance test, and hyperinsulinemic--euglycemic clamp), and imaging studies (magnetic resonance imaging (MRI), DEXA). Using quantitative real-time-PCR; adiponectin, PPARγ2, TNFα, and leptin mRNA were measured. Based on a hepatic fat content (hepatic fat fraction, HFF) >5.5%, measured by fast MRI, the subjects were divided into low and high HFF group. In addition to the hypoadiponectinemia in the high HFF group, we found that the expression of adiponectin as well as PPARγ2 in the SAT was significantly decreased in this group. No differences were noted for TNFα and leptin plasma or mRNA levels between the groups. An inverse relationship was observed between adiponectin or PPARγ2 expression and hepatic fat content, whereas, adiponectin expression was positively related to PPARγ2 expression. Independent of overall obesity, a reduced expression of adiponectin and PPARγ2 in the abdominal SAT is associated with high liver fat content, as well as with insulin resistance in obese adolescents.
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Affiliation(s)
- Romy Kursawe
- Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Deepak Narayan
- Department of Plastic Surgery, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Anna M.G. Cali
- Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Melissa Shaw
- Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Bridget Pierpont
- Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Gerald I. Shulman
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
- Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Sonia Caprio
- Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA
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Ercin CN, Dogru T, Tapan S, Kara M, Haymana C, Karadurmus N, Karslioglu Y, Acikel C. Plasma apelin levels in subjects with nonalcoholic fatty liver disease. Metabolism 2010; 59:977-81. [PMID: 20045153 DOI: 10.1016/j.metabol.2009.10.019] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2009] [Revised: 10/21/2009] [Accepted: 10/23/2009] [Indexed: 12/20/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD), one of the most common forms of chronic liver disease, is closely associated with obesity and insulin resistance. Recent studies suggest that apelin, a newly described adipokine, is associated with hyperinsulinemia and inflammation. The aim of the study was to investigate plasma apelin concentrations in biopsy-proven NAFLD patients who had no metabolic confounders and also to search for the association of apelin with adiponectin, body mass index (BMI), and insulin sensitivity. Fifty male patients with NAFLD and 30 healthy male controls were enrolled. Apelin was measured along with BMI, lipids, glucose, insulin, adiponectin, and homeostasis model assessment (HOMA) of insulin resistance indexes. Plasma apelin levels were significantly higher and adiponectin levels were lower in NAFLD patients when compared with the controls (P < .001 and P = .013, respectively). In multivariate analysis adjusted for BMI and HOMA indexes, the differences in apelin and adiponectin disappeared in the 2 groups (P = .3 and P = .1, respectively). In addition, apelin levels were positively correlated with BMI (r = 0.29, P = .05) and HOMA indexes (r = 0.4, P = .008) in subjects with NAFLD. The results of this preliminary study suggest that plasma apelin levels are not altered in nondiabetic and normotensive male subjects with NAFLD.
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Affiliation(s)
- Cemal Nuri Ercin
- Department of Gastroenterology, Gulhane School of Medicine, Etlik, Ankara, Turkey.
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Lonardo A, Caldwell SH, Loria P. Clinical physiology of NAFLD: a critical overview of pathogenesis and treatment. Expert Rev Endocrinol Metab 2010; 5:403-423. [DOI: 10.1586/eem.10.5] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2025]
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Polyzos SA, Kountouras J, Zavos C, Tsiaousi E. The role of adiponectin in the pathogenesis and treatment of non-alcoholic fatty liver disease. Diabetes Obes Metab 2010; 12:365-83. [PMID: 20415685 DOI: 10.1111/j.1463-1326.2009.01176.x] [Citation(s) in RCA: 195] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is recognized as the most common type of chronic liver disease in Western countries and the leading cause of cryptogenic cirrhosis. Insulin resistance (IR) is a key factor in the pathogenesis of NAFLD, the latter being considered as the hepatic component of IR or metabolic syndrome (MetS). Although the pathogenesis of NAFLD is not fully elucidated, a complex interaction between adipokines and cytokines produced by adipocytes and/or inflammatory cells infiltrating adipose tissue appears to play a crucial role in MetS and NAFLD. Adiponectin is the most abundant and adipose-specific adipokine. In the liver, adiponectin acts through the activation of 5-AMP-activated protein kinase and peroxisome proliferator-activated receptor-alpha pathways and inhibition of toll-like receptor-4 mediated signalling. There is an evidence that adiponectin decreases hepatic and systematic IR and attenuates liver inflammation and fibrosis. Adiponectin generally predicts steatosis grade and severity of NAFLD, but it remains to be addressed to what extent this is a direct effect or related to the presence of more severe IR. Although there is no proven pharmacotherapy for the treatment of NAFLD, recent therapeutic strategies have focused on the indirect upregulation of adiponectin through the administration of various therapeutic agents and/or lifestyle modifications. Weight loss, through diet, lifestyle changes and/or medications including orlistat, sibutramine, rimonabant or bariatric surgery, increase adiponectin and may improve liver histology. Insulin sensitizers, including pioglitazone and rosiglitazone, and lipid-lowering agents, including statins and fibrates, also upregulate adiponectin and ameliorate liver histology. The wider use of new treatment approaches appears to signal the dawn of a new era in the management of NAFLD. In this adiponectin-focused review, the pathogenetic role and the potential therapeutic benefits of adiponectin in NAFLD are systematically analysed.
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Affiliation(s)
- Stergios A Polyzos
- Second Medical Clinic, Medical School, Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki, Greece.
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Bauer S, Weigert J, Neumeier M, Wanninger J, Schäffler A, Luchner A, Schnitzbauer AA, Aslanidis C, Buechler C. Low-abundant adiponectin receptors in visceral adipose tissue of humans and rats are further reduced in diabetic animals. Arch Med Res 2010; 41:75-82. [PMID: 20470935 DOI: 10.1016/j.arcmed.2010.02.010] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2009] [Accepted: 01/12/2010] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIMS Adipose tissue is an endocrine organ that releases various proteins that may also exert autocrine/paracrine effects. The antidiabetic adipokine adiponectin acts through two receptors, AdipoR1 and AdipoR2, but so far mainly mRNA expression has been measured in adipocytes and adipose tissues. Therefore, we aimed to analyze AdipoR1 and AdipoR2 proteins in adipocytes and paired samples of subcutaneous and visceral adipocytes/adipose tissue. METHODS AdipoR1 and AdipoR2 mRNA and protein expression were determined in adipocytes and paired samples of subcutaneous and visceral adipose tissue of humans and rats. RESULTS AdipoR1 and AdipoR2 proteins were similarly abundant in preadipocytes and mature adipocytes despite an induction of mRNA expression during differentiation. Differentiation of 3T3-L1 cells in the presence of palmitic acid did not alter adiponectin receptor proteins but metformin and fenofibrate upregulated AdipoR2 within 24 h of incubation. AdipoR2 protein was significantly lower in human visceral compared to subcutaneous fat, and both receptors were reduced in visceral adipocytes. In rat tissues both receptors were reduced in visceral fat. In diabetic animals AdipoR2 protein, but not mRNA, was lower in both fat depots compared to similarly obese rats with normal glucose disposal. AdipoR1 was only reduced in subcutaneous adipose tissue of diabetic animals where mRNA expression was induced. CONCLUSIONS These data indicate that mRNA expression is not suitable to predict adiponectin receptor protein. Low adiponectin receptors in visceral adipocytes and adipose tissue and further suppression in adipose tissue of insulin-resistant animals indicate disturbed adiponectin bioactivity.
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Affiliation(s)
- Sabrina Bauer
- Department of Internal Medicine I, Regensburg University Hospital, D-93042 Regensburg, Germany
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Hepatic adiponectin receptors (ADIPOR) 1 and 2 mRNA and their relation to insulin resistance in obese humans. Int J Obes (Lond) 2010; 34:846-51. [PMID: 20125105 DOI: 10.1038/ijo.2010.7] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Adiponectin signalling attenuates insulin resistance (IR) and steatosis hepatis in animal models. As adiponectin receptor (ADIPOR)1 and ADIPOR2 are critical components in the adiponectin signalling cascade, we studied hepatic ADIPOR1/2 mRNA levels in humans and their relation to IR. DESIGN We determined metabolic risk factors and levels of hepatic mRNA transcribed from ADIPOR1, ADIPOR2 and FOXO1, a putative up-stream regulator, in 43 and 34 obese subjects with low and high homeostasis model assessment-IR, respectively. RESULTS Plasma adiponectin and metabolic risk factors showed associations with IR as expected. Both hepatic ADIPOR1 and ADIPOR2 mRNA expression levels were higher in insulin-resistant subjects (P<0.0035). ADIPOR1 mRNA correlated with FOXO1 mRNA in obese insulin resistant (P=0.0034), but not insulin-sensitive subjects, while no correlations of ADIPOR2 with FOXO1 mRNA were noted. FOXO1 enhanced transcription from the ADIPOR1, but not the ADIPOR2 promoter in HepG2 cells. CONCLUSION Increased hepatic ADIPOR1 and ADIPOR2 mRNA in insulin-resistant obese subjects may, at least in part, reflect a compensatory mechanism for reduced plasma adiponectin. FOXO1 may contribute to enhanced ADIPOR1, but not ADIPOR2 transcription in IR.
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Abstract
Nonalcoholic steatohepatitis (NASH) is a pathological condition characterized by macrovesicular steatosis, necroinflammation, loss of hepatocytes and fibrosis. NASH is often associated with type 2 diabetes mellitus, hypertension, hyperlipoproteinemia and obesity. Recent studies emphasize the role of insulin resistance, oxidative stress and subsequent lipid peroxidation, proinflammatory cytokines, adipokines and mitochondrial dysfunction in the development and progression of NASH. In this article, we will review the role of insulin resistance, oxidative stress and subsequent lipid peroxidation, mitochondrial dysfunction, proinflammatory cytokines, adipokines such as resistin, leptin, adiponectin and PPAR-α, apoptosis, NF kappa B, SREBP-1c, endotoxaemia, and iron overload in the pathogenesis of NASH. The pathogenesis of NASH is thought to be related mainly with insulin resistance and oxidative stress and subsequent lipid peroxidation. Adipocytokines also play an important role in the pathogenesis of NASH through complex and interactive paracrine and endocrine mechanisms. Understanding of the mechanisms responsible for the pathogenesis of NASH has important implications for the treatment of NASH.
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Rahman SM, Qadri I, Janssen RC, Friedman JE. Fenofibrate and PBA prevent fatty acid-induced loss of adiponectin receptor and pAMPK in human hepatoma cells and in hepatitis C virus-induced steatosis. J Lipid Res 2009; 50:2193-202. [PMID: 19502591 DOI: 10.1194/jlr.m800633-jlr200] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Adiponectin receptors play a key role in steatosis and inflammation; however, very little is known about regulation of adiponectin receptors in liver. Here, we examined the effects of palmitate loading, endoplasmic reticulum (ER) stress, and the hypolipidemic agent fenofibrate on adiponectin receptor R2 (AdipoR2) levels and AMP-activated protein kinase (AMPK) in human hepatoma Huh7 cells and in Huh.8 cells, a model of hepatitis C-induced steatosis. Palmitate treatment reduced AdipoR2 protein and basal AMPK phosphorylation in Huh7 cells. Fenofibrate treatment preserved AdipoR2 and phosphorylated AMPK (pAMPK) levels in palmitate-treated cells accompanied by reduced triglyceride (TG) accumulation and less activation of ER stress markers CCAAT/enhancer binding (C/EBPbeta) and eukaryotic translation initiation factor 2 alpha. ER stress agents thapsigargin and tunicamycin suppressed AdipoR2 and pAMPK levels in Huh7 cells, while fenofibrate and the chemical chaperone 4-phenylbutyrate (PBA) prevented these changes. AdipoR2 levels were lower in Huh.8 cells and fenofibrate treatment increased AdipoR2 while reducing activation of c-Jun N-terminal kinase and C/EBPbeta expression without changing TG levels. Taken together, these results suggest that fatty acids and ER stress reduce AdipoR2 protein and pAMPK levels, while fenofibrate and PBA might be important therapeutic agents to correct lipid- and ER stress-mediated loss of AdipoR2 and pAMPK associated with nonalcoholic steatohepatitis.
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Adipokines in nonalcoholic steatohepatitis: from pathogenesis to implications in diagnosis and therapy. Mediators Inflamm 2009; 2009:831670. [PMID: 19753129 PMCID: PMC2694309 DOI: 10.1155/2009/831670] [Citation(s) in RCA: 94] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2009] [Accepted: 04/06/2009] [Indexed: 12/13/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and can vary from benign steatosis to end-stage liver disease. The pathogenesis of non-alcoholic steatohepatitis (NASH) is currently thought to involve a multiple-hit process with the first hit being the accumulation of liver fat which is followed by the development of necroinflammation and fibrosis. There is mounting evidence that cytokines secreted from adipose tissue, namely, adipokines, are implicated in the pathogenesis and progression of NAFLD. In the current review, we explore the role of these adipokines, particularly leptin, adiponectin, resistin, tumor necrosis factor-a, and interleukin-6 in NASH, as elucidated in experimental models and clinical practice. We also comment on their potential use as noninvasive markers for differentiating simple fatty liver from NASH as well as on their potential future therapeutic role in patients with NASH.
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