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Mao Z, Zhao J, Cui F, Li Z, Cao J, Zhou J, Hou M, Qian Z. STUB1 increases adiponectin expression by inducing ubiquitination and degradation of NR2F2, thereby reducing hepatic stellate cell activation and alleviating non-alcoholic fatty liver disease. Tissue Cell 2024; 88:102345. [PMID: 38471267 DOI: 10.1016/j.tice.2024.102345] [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: 12/24/2023] [Revised: 02/28/2024] [Accepted: 02/29/2024] [Indexed: 03/14/2024]
Abstract
BACKGROUND Adiponectin (APN) has exhibited ameliorating effects on non-alcoholic fatty liver disease (NAFLD). This study investigates the roles of APN and its regulatory molecules in hepatic stellate cell (HSC) activation and the progression of NAFLD. METHODS Mice were subjected to a high-fat diet (HFD) to establish NAFLD models. Liver tissue was examined for lipid metabolism, fibrosis, and inflammation. Mouse 3T3-L1 adipocytes were exposed to palmitic acid (PA) to mimic a high-fat environment. The conditioned medium (CM) from adipocytes was collected for the culture of isolated mouse HSCs. Gain- or loss-of-function studies of APN, nuclear receptor subfamily 2 group F member 2 (NR2F2), and STIP1 homology and U-box containing protein 1 (STUB1) were performed to analyze their roles in NAFLD and HSC activation in vivo and in vitro. RESULTS APN expression was poorly expressed in HFD-fed mice and PA-treated 3T3-L1 adipocytes, which was attributed to the transcription inhibition mediated by NR2F2. Silencing of NR2F2 restored the APN expression, ameliorating liver steatosis, fibrosis, and inflammatory cytokine infiltration in mouse livers and reducing HSC activation. Similarly, the NR2F2 silencing condition reduced HSC activation in vitro. However, these effects were counteracted by artificial APN silencing. STUB1 facilitated the ubiquitination and protein degradation of NR2F2, and its upregulation mitigated NAFLD-like symptoms in mice and HSC activation, effects reversed by the NR2F2 overexpression. CONCLUSION This study highlights the role of STUB1 in reducing HSC activation and alleviating NAFLD by attenuating NR2F2-mediated transcriptional repression of APN.
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Affiliation(s)
- Zheng Mao
- Department of Clinical Laboratory, Wuhu Hospital Affiliated to Anhui University of Science and Technology (The First People's Hospital of Wuhu), Wuhu, Anhui 241000, PR China
| | - Jindong Zhao
- Department of Endocrinology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui 230038, PR China
| | - Fan Cui
- Department of Clinical Laboratory, Wuhu Hospital Affiliated to Anhui University of Science and Technology (The First People's Hospital of Wuhu), Wuhu, Anhui 241000, PR China
| | - Zhen Li
- Department of Clinical Laboratory, Wuhu Hospital Affiliated to Anhui University of Science and Technology (The First People's Hospital of Wuhu), Wuhu, Anhui 241000, PR China
| | - Jinjin Cao
- Department of Clinical Laboratory, Wuhu Hospital Affiliated to Anhui University of Science and Technology (The First People's Hospital of Wuhu), Wuhu, Anhui 241000, PR China
| | - Jingjing Zhou
- Department of Clinical Laboratory, Wuhu Hospital Affiliated to Anhui University of Science and Technology (The First People's Hospital of Wuhu), Wuhu, Anhui 241000, PR China
| | - Mingliang Hou
- Department of Clinical Laboratory, Wuhu Hospital Affiliated to Anhui University of Science and Technology (The First People's Hospital of Wuhu), Wuhu, Anhui 241000, PR China
| | - Zengkun Qian
- Department of Clinical Laboratory, Wuhu Hospital Affiliated to Anhui University of Science and Technology (The First People's Hospital of Wuhu), Wuhu, Anhui 241000, PR China.
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Asahara N, Okada-Iwabu M, Iwabu M, Wada K, Oka K, Yamauchi T, Kadowaki T. A monoclonal antibody activating AdipoR for type 2 diabetes and nonalcoholic steatohepatitis. SCIENCE ADVANCES 2023; 9:eadg4216. [PMID: 37948516 PMCID: PMC10637737 DOI: 10.1126/sciadv.adg4216] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 10/13/2023] [Indexed: 11/12/2023]
Abstract
Adiponectin receptors, AdipoR1 and AdipoR2 are promising targets for the prevention and treatment of metabolic diseases. In this study, we aimed to establish agonistic antibodies against AdipoR1 and AdipoR2 with a long enough half-life to provide a means of improving poor medication adherence associated with preclinical small-molecule AdipoR agonists or existing antidiabetic drugs. Monoclonal antibodies were obtained by immunizing AdipoR knockout mice with human AdipoR-expressing cells. Of the antibodies shown to bind to both, an agonist antibody was obtained, which exhibited adenosine 5'-monophosphate-activated protein kinase-activating properties such as adiponectin and was named AdipoR-activating monoclonal antibody (AdipoRaMab). AdipoRaMab ameliorated glucose intolerance in high-fat diet-fed mice, which was not observed in AdipoR1·AdipoR2 double knockout mice. AdipoRaMab exhibited anti-inflammatory and antifibrotic effects in the nonalcoholic steatohepatitis (NASH) model, indicating its therapeutic potential in diabetes and in NASH. In addition, the results of this study indicated that AdipoRaMab may exert therapeutic effects even in a once-monthly dosing regimen through its humanization.
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Affiliation(s)
- Naomi Asahara
- Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan
| | - Miki Okada-Iwabu
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
- Laboratory for Advanced Research on Pathophysiology of Metabolic Diseases, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Masato Iwabu
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
- Department of Endocrinology, Metabolism and Nephrology, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan
| | - Kouichi Wada
- Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Shonan Health Innovation Park, 2-26-1, Muraoka-Higashi, Fujisawa, Kanagawa 251-8555, Japan
| | - Kozo Oka
- Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Shonan Health Innovation Park, 2-26-1, Muraoka-Higashi, Fujisawa, Kanagawa 251-8555, Japan
| | - Toshimasa Yamauchi
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
- Laboratory for Advanced Research on Pathophysiology of Metabolic Diseases, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Takashi Kadowaki
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
- Laboratory for Advanced Research on Pathophysiology of Metabolic Diseases, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
- Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo 105-8470, Japan
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Luo K, Chen Y, Fang S, Wang S, Wu Z, Li H. Study on inflammation and fibrogenesis in MAFLD from 2000 to 2022: a bibliometric analysis. Front Endocrinol (Lausanne) 2023; 14:1231520. [PMID: 37720529 PMCID: PMC10500306 DOI: 10.3389/fendo.2023.1231520] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 08/08/2023] [Indexed: 09/19/2023] Open
Abstract
Chronic inflammation and fibrosis are significant factors in the pathogenesis of metabolic-associated fatty liver disease (MAFLD). In this study, we conducted a bibliometric analysis of publications on inflammation and fibrogenesis in MAFLD, with a focus on reporting publication trends. Our findings indicate that the USA and China are the most productive countries in the field, with the University of California San Diego being the most productive institution. Over the past 23 years, Prof. Diehl AM has published 25 articles that significantly contributed to the research community. Notably, the research focus of the field has shifted from morbid obesity and adiponectin to metabolic syndrome, genetics, and microbiome. Our study provides a comprehensive and objective summary of the historical characteristics of research on inflammation and fibrogenesis in MAFLD, which will be of interest to scientific researchers in this field.
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Affiliation(s)
- Kuanhong Luo
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yang Chen
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuzheng Fang
- College of Art and Sciences, Washington University in St. Louis, St. Louis, MO, United States
| | - Siqi Wang
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhixin Wu
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huiqing Li
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Sumińska M, Podgórski R, Fichna P, Mazur A, Fichna M. The Impact of Obesity on the Excretion of Steroid Metabolites in Boys and Girls: A Comparison with Normal-Weight Children. Nutrients 2023; 15:1734. [PMID: 37049573 PMCID: PMC10097123 DOI: 10.3390/nu15071734] [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: 02/23/2023] [Revised: 03/29/2023] [Accepted: 03/30/2023] [Indexed: 04/05/2023] Open
Abstract
Obesity in childhood is associated with several steroid changes, which result from excess body mass. The aim of this study was to evaluate steroid metabolism in children with obesity compared with those with normal weight, especially in relation to sex and puberty progress. We analyzed the clinical data of 191 children, aged between 5 and 18 years, with 115 affected (64 girls and 51 boys) and 76 unaffected (35 girls and 41 boys) by obesity. Routine clinical assessment and pubertal stage evaluation based upon Tanner's scale were performed. In addition, to evaluate the impact of puberty, children with pre-adolescence and advanced puberty were divided into separate subgroups. Then, 24 h urine steroid excretion profiles were analyzed by gas chromatography/mass spectrometry. Significant differences in the excretion of steroid metabolites were found between normal weight children and children with obesity, especially in the prepubertal cohort. In this group, we observed enhanced activity in all the pathways of adrenal steroidogenesis. Raised excretion of mineralocorticoid derivatives such as tetrahydro-11-deoxycorticosterone, tetrahydrocorticosterone, and 5α-tetrahydrocorticosterone supported increased activity of this track. No significant differences were detected in the excreted free forms of cortisol and cortisone, while the excretion of their characteristic tetrahydro-derivatives was different. In pre-adolescent children with obesity, α-cortol and especially α-cortolone appeared to be excreted more abundantly than β-cortol or β-cortolone. Furthermore, in children with obesity, we observed elevated androgen excretion with an enhanced backdoor pathway. As puberty progressed, remarkable reduction in the differences between adolescents with and without obesity was demonstrated.
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Affiliation(s)
- Marta Sumińska
- Department of Pediatric Diabetes, Auxology and Obesity, Institute of Pediatrics, Poznan University of Medical Sciences, 60-572 Poznan, Poland
- Doctoral School, Poznan University of Medical Sciences, 60-812 Poznan, Poland
| | - Rafał Podgórski
- Centre for Innovative Research in Medical and Natural Sciences, University of Rzeszow, 35-310 Rzeszow, Poland
- Department of Biochemistry, Institute of Medical Sciences, College of Medical Sciences, University of Rzeszow, 35-959 Rzeszow, Poland
| | - Piotr Fichna
- Department of Pediatric Diabetes, Auxology and Obesity, Institute of Pediatrics, Poznan University of Medical Sciences, 60-572 Poznan, Poland
| | - Artur Mazur
- Department of Pediatrics, Childhood Endocrinology and Diabetes, Collegium of Medical Sciences, University of Rzeszow, 35-959 Rzeszow, Poland
| | - Marta Fichna
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, 60-355 Poznan, Poland
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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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Rajesh Y, Sarkar D. Association of Adipose Tissue and Adipokines with Development of Obesity-Induced Liver Cancer. Int J Mol Sci 2021; 22:ijms22042163. [PMID: 33671547 PMCID: PMC7926723 DOI: 10.3390/ijms22042163] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/01/2021] [Accepted: 02/02/2021] [Indexed: 12/20/2022] Open
Abstract
Obesity is rapidly dispersing all around the world and is closely associated with a high risk of metabolic diseases such as insulin resistance, dyslipidemia, and nonalcoholic fatty liver disease (NAFLD), leading to carcinogenesis, especially hepatocellular carcinoma (HCC). It results from an imbalance between food intake and energy expenditure, leading to an excessive accumulation of adipose tissue (AT). Adipocytes play a substantial role in the tumor microenvironment through the secretion of several adipokines, affecting cancer progression, metastasis, and chemoresistance via diverse signaling pathways. AT is considered an endocrine organ owing to its ability to secrete adipokines, such as leptin, adiponectin, resistin, and a plethora of inflammatory cytokines, which modulate insulin sensitivity and trigger chronic low-grade inflammation in different organs. Even though the precise mechanisms are still unfolding, it is now established that the dysregulated secretion of adipokines by AT contributes to the development of obesity-related metabolic disorders. This review focuses on several obesity-associated adipokines and their impact on obesity-related metabolic diseases, subsequent metabolic complications, and progression to HCC, as well as their role as potential therapeutic targets. The field is rapidly developing, and further research is still required to fully understand the underlying mechanisms for the metabolic actions of adipokines and their role in obesity-associated HCC.
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Affiliation(s)
- Yetirajam Rajesh
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA;
| | - Devanand Sarkar
- Massey Cancer Center, Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine (VIMM), Virginia Commonwealth University, Richmond, VA 23298, USA
- Correspondence: ; Tel.: +1-804-827-2339
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Lonardo A, Leoni S, Alswat KA, Fouad Y. History of Nonalcoholic Fatty Liver Disease. Int J Mol Sci 2020; 21:5888. [PMID: 32824337 PMCID: PMC7460697 DOI: 10.3390/ijms21165888] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 08/10/2020] [Accepted: 08/12/2020] [Indexed: 12/15/2022] Open
Abstract
Based on the assumption that characterizing the history of a disease will help in improving practice while offering a clue to research, this article aims at reviewing the history of nonalcoholic fatty liver disease (NAFLD) in adults and children. To this end, we address the history of NAFLD histopathology, which begins in 1980 with Ludwig's seminal studies, although previous studies date back to the 19th century. Moreover, the principal milestones in the definition of genetic NAFLD are summarized. Next, a specific account is given of the evolution, over time, of our understanding of the association of NAFLD with metabolic syndrome, spanning from the outdated concept of "NAFLD as a manifestation of the Metabolic Syndrome", to the more appropriate consideration that NAFLD has, with metabolic syndrome, a mutual and bi-directional relationship. In addition, we also report on the evolution from first intuitions to more recent studies, supporting NAFLD as an independent risk factor for cardiovascular disease. This association probably has deep roots, going back to ancient Middle Eastern cultures, wherein the liver had a significance similar to that which the heart holds in contemporary society. Conversely, the notions that NAFLD is a forerunner of hepatocellular carcinoma and extra-hepatic cancers is definitely more modern. Interestingly, guidelines issued by hepatological societies have lagged behind the identification of NAFLD by decades. A comparative analysis of these documents defines both shared attitudes (e.g., ultrasonography and lifestyle changes as the first approaches) and diverging key points (e.g., the threshold of alcohol consumption, screening methods, optimal non-invasive assessment of liver fibrosis and drug treatment options). Finally, the principal historical steps in the general, cellular and molecular pathogenesis of NAFLD are reviewed. We conclude that an in-depth understanding of the history of the disease permits us to better comprehend the disease itself, as well as to anticipate the lines of development of future NAFLD research.
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Affiliation(s)
- Amedeo Lonardo
- Ospedale Civile di Baggiovara, UOC Medicina Metabolica, Dipartimento di Medicina Interna Generale, d’Urgenza e post Acuzie, Azienda Ospedaliero-Universitaria di Modena, Via Giardini 1135, 41125 Modena, Italy
| | - Simona Leoni
- Internal Medicine Unit, Department of Digestive Diseases, S.Orsola-Malpighi Hospital, Via Massarenti 9, 40136 Bologna, Italy;
| | - Khalid A. Alswat
- Liver Research Center, Department of Medicine, College of Medicine, King Saud University, Riyadh 11322, Saudi Arabia;
| | - Yasser Fouad
- Department of Gastroenterology, Hepatology and Endemic Medicine, Faculty of Medicine, Minia University, Minya 19111, Egypt;
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Heydari M, Cornide-Petronio ME, Jiménez-Castro MB, Peralta C. Data on Adiponectin from 2010 to 2020: Therapeutic Target and Prognostic Factor for Liver Diseases? Int J Mol Sci 2020; 21:5242. [PMID: 32718097 PMCID: PMC7432057 DOI: 10.3390/ijms21155242] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [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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Affiliation(s)
- Misaq Heydari
- Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), 08036 Barcelona, Spain; (M.H.); (M.E.C.-P.)
| | | | - Mónica B. Jiménez-Castro
- Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), 08036 Barcelona, Spain; (M.H.); (M.E.C.-P.)
| | - Carmen Peralta
- Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), 08036 Barcelona, Spain; (M.H.); (M.E.C.-P.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 08036 Barcelona, Spain
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Jang HH, Bae JH, Kim MJ, Park MY, Kim HR, Lee YM. Agrimonia pilosa Ledeb. Ameliorates Hyperglycemia and Hepatic Steatosis in Ovariectomized Rats Fed a High-Fat Diet. Nutrients 2020; 12:nu12061631. [PMID: 32492866 PMCID: PMC7352636 DOI: 10.3390/nu12061631] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 05/18/2020] [Accepted: 05/27/2020] [Indexed: 12/14/2022] Open
Abstract
Estrogen deficiency is associated with obesity, dyslipidemia, and increased insulin resistance in postmenopausal women. An efficient therapeutic agent prevents or improves postmenopausal conditions induced by estrogen deficiency. Here, we investigated the effects of aqueous Agrimonia pilosa Ledeb. extract on glucose and lipid metabolism in ovariectomized rats fed a high-fat diet (HFD). Female Sprague-Dawley rats were sham-operated or ovariectomized, and 3 weeks later were assigned to the following groups: sham-operated + HFD (S); ovariectomized + HFD (OVX); and ovariectomized + HFD with 0.5% A. pilosa aqueous extract (OVX + 0.5A) groups. Ovariectomy significantly increased body weight and dietary intake relative to the S group. However, A. pilosa treatment did not significantly affect weight gain or dietary intake. Blood triacylglycerol, total cholesterol, and low-density lipoprotein cholesterol levels tended to decrease in the A. pilosa-supplemented group. Blood glucose levels were significantly lower in the OVX + 0.5A group than those in the OVX group. Blood adiponectin and insulin concentrations increased significantly after A. pilosa treatment in the ovariectomized group. A. pilosa supplementation tended to decrease liver weights and prevented lipid accumulation. These effects correlated with reduced hepatic expression of lipogenesis-related genes (fatty acid synthase, acetyl-coenzyme A carboxylase alpha, and 3-hydroxy-3-methylglutaryl-coenzyme A reductase). Therefore, A. pilosa may improve metabolic disorders in ovariectomized rats.
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Affiliation(s)
- Hwan-Hee Jang
- Functional Food Division, National Institute of Agricultural Sciences, Rural Development Administration, Wanju 55365, Korea; (H.-H.J.); (J.H.B.); (M.-J.K.); (M.Y.P.); (H.R.K.)
| | - Ji Hyun Bae
- Functional Food Division, National Institute of Agricultural Sciences, Rural Development Administration, Wanju 55365, Korea; (H.-H.J.); (J.H.B.); (M.-J.K.); (M.Y.P.); (H.R.K.)
| | - Mi-Ju Kim
- Functional Food Division, National Institute of Agricultural Sciences, Rural Development Administration, Wanju 55365, Korea; (H.-H.J.); (J.H.B.); (M.-J.K.); (M.Y.P.); (H.R.K.)
| | - Mi Young Park
- Functional Food Division, National Institute of Agricultural Sciences, Rural Development Administration, Wanju 55365, Korea; (H.-H.J.); (J.H.B.); (M.-J.K.); (M.Y.P.); (H.R.K.)
| | - Haeng Ran Kim
- Functional Food Division, National Institute of Agricultural Sciences, Rural Development Administration, Wanju 55365, Korea; (H.-H.J.); (J.H.B.); (M.-J.K.); (M.Y.P.); (H.R.K.)
| | - Young-Min Lee
- Division of Applied Food System, Major of Food and Nutrition, Seoul Women’s University, Seoul 01797, Korea
- Correspondence: ; Tel.: +82-2-970-5642
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Levin LM, Völzke H, Lerch MM, Kühn JP, Nauck M, Friedrich N, Zylla S. Associations of circulating chemerin and adiponectin concentrations with hepatic steatosis. Endocr Connect 2019; 8:1097-1107. [PMID: 31265993 PMCID: PMC6652250 DOI: 10.1530/ec-19-0300] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 07/02/2019] [Indexed: 12/20/2022]
Abstract
OBJECTIVE Chemerin and adiponectin are adipokines assumed to be involved in the development of metabolic syndrome-related phenotypes like hepatic steatosis. We aimed to evaluate the associations of circulating chemerin and adiponectin concentrations with liver enzymes, liver fat content, and hepatic steatosis in the general population. METHODS Data of 3951 subjects from the population-based Study of Health in Pomerania (SHIP-TREND) were used. Hepatic steatosis was assumed when either a hyperechogenic liver (assessed via ultrasound) or a magnetic resonance imaging (MRI)-quantified liver fat content >5% was present. Adjusted sex-specific quantile and logistic regression models were applied to analyze the associations of chemerin and adiponectin with liver enzymes, liver fat content and hepatic steatosis. RESULTS The observed associations of chemerin and adiponectin with liver enzymes were very divergent depending on sex, fasting status and the specific enzyme. More consistent results were seen in the analyses of these adipokines in relation to MRI-quantified liver fat content. Here, we observed inverse associations to adiponectin in both sexes as well as a positive (men) or U-shaped (women) association to chemerin. Similarly, the MRI-based definition of hepatic steatosis revealed strongly consistent results: in both sexes, high chemerin concentrations were associated with higher odds of hepatic steatosis, whereas high adiponectin concentrations were associated with lower odds. CONCLUSION Our results suggest a role of these adipokines in the pathogenesis of hepatic steatosis independent of metabolic or inflammatory disorders. However, experimental studies are needed to further clarify the underlying mechanisms and the inter-play between adipokine concentrations and hepatic steatosis.
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Affiliation(s)
- Lena-Maria Levin
- Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Henry Völzke
- Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
- DZHK (German Centre for Cardiovascular Research), Greifswald, Germany
- DZD (German Center for Diabetes Research), Greifswald, Germany
| | - Markus M Lerch
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Jens-Peter Kühn
- Department of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany
- Institute and Policlinic for Radiology and Interventional Radiology, University Hospital, Carl-Gustav-Carus University Dresden, Dresden, Germany
| | - Matthias Nauck
- Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
- DZHK (German Centre for Cardiovascular Research), Greifswald, Germany
| | - Nele Friedrich
- Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
- DZHK (German Centre for Cardiovascular Research), Greifswald, Germany
| | - Stephanie Zylla
- Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
- DZHK (German Centre for Cardiovascular Research), Greifswald, Germany
- Correspondence should be addressed to S Zylla:
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Saito H, Tanaka T, Sugahara M, Tanaka S, Fukui K, Wakashima T, Nangaku M. Inhibition of prolyl hydroxylase domain (PHD) by JTZ-951 reduces obesity-related diseases in the liver, white adipose tissue, and kidney in mice with a high-fat diet. J Transl Med 2019; 99:1217-1232. [PMID: 30952940 DOI: 10.1038/s41374-019-0239-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Revised: 01/16/2019] [Accepted: 01/28/2019] [Indexed: 12/11/2022] Open
Abstract
The epidemic of obesity and its complications is rapidly increasing worldwide. Recent drug discoveries established the utility of prolyl hydroxylase domain (PHD) inhibitors as stabilizers of hypoxia-inducible factors (HIFs) in vivo, which are currently in human clinical studies for the treatment of anemia in chronic kidney disease (CKD). These studies suggest a role for PHD inhibitors in ameliorating obesity and hyperlipidemia. We hypothesized that HIF activation using a PHD inhibitor, JTZ-951, protects from obesity-related diseases in the white adipose tissue (WAT), liver, and kidney in mice fed with high-fat diet (HFD). Eight-week-old, C57BL/6J mice were fed with HFD for 20 weeks with or without JTZ-951(0.005%; mixed in chow). Body weight and plasma non-high-density lipoprotein (HDL) cholesterol levels were significantly lower in the JTZ-951 group as compared with the vehicle group. PHD inhibition improved liver steatosis, macrophage infiltration into WAT and adipocyte fibrosis. In the kidney, PHD inhibition reduced albuminuria. Histologically, the number of F4/80- positive infiltrating macrophages and mesangial expansion were milder in the JTZ-951 group. Relative mRNA expression of adiponectin in WAT was higher in the JTZ-951-treated group and inversely correlated with hepatic steatosis score, adipocyte macrophage aggregation, and albuminuria. Activation of HIF ameliorates multiple obesity-related consequences in mice with HFD. The results of the present study offer the promising view that pharmacological PHD inhibition may be beneficial for the treatment of obesity-related diseases that can be ameliorated by weight loss.
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Affiliation(s)
- Hisako Saito
- Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Tetsuhiro Tanaka
- Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
| | - Mai Sugahara
- Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Shinji Tanaka
- Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Kenji Fukui
- Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.,Biological and Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc, Osaka, Japan
| | - Takeshi Wakashima
- Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.,Biological and Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc, Osaka, Japan
| | - Masaomi Nangaku
- Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
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12
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Karonova T, Belyaeva O, Jude EB, Tsiberkin A, Andreeva A, Grineva E, Pludowski P. Serum 25(OH)D and adipokines levels in people with abdominal obesity. J Steroid Biochem Mol Biol 2018; 175:170-176. [PMID: 27629594 DOI: 10.1016/j.jsbmb.2016.09.005] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Revised: 09/02/2016] [Accepted: 09/10/2016] [Indexed: 11/29/2022]
Abstract
Abdominal obesity is a risk factor for cardiovascular disease and diabetes mellitus and has been associated with vitamin D deficiency. Some studies have suggested an association between obesity and adipokine levels as well as low serum 25-hydroxyvitamin D (25(OH)D) level but the underlying mechanisms of the interlink between vitamin D status and serum leptin and adiponectin concentrations are still disputed. We included 435 residents (132 males) from St. Petersburg, Russia into this study. All subjects had physical examination and demographics noted. Blood was collected after an overnight fast and plasma glucose, insulin, serum lipids, 25(OH)D and adipokines (adiponectin and leptin) concentrations were determined at baseline in all participants. Abdominal obesity was diagnosed in 310 (71.3%) subjects (251 females and 59 males). Vitamin D insufficiency and deficiency were found in 314 (72.2%) subjects. Mean (95% CI) age, body mass index (BMI) and serum 25(OH)D for the cohort were 47.6±11.3years; 28.7±0.2kg/m2 and 62.5±24.3nmol/l respectively. Serum 25(OH)D level inversely correlated with body weight, waist circumference (WC) and BMI in females but not in males, was lower in diabetic than non-diabetic subjects, and was not significantly different in subjects with and without MetS. WC was positively correlated with leptin and negatively correlated with adiponectin. We found correlation between leptin and serum 25(OH)D level (r=-0.15, p=0.01) but this finding was a characteristic seen only in women. Our study showed a high prevalence of abdominal obesity, vitamin D deficiency and insufficiency in residents from North-West region of Russia, close association between adipokine (leptin, adiponectin) concentrations as well as vitamin D status and body composition (WC, BMI). However in our study the interlink between leptin level and 25(OH)D was found only in females. Further investigations are required to study the relationship between serum 25(OH)D level, obesity and serum adipokine levels.
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Affiliation(s)
- T Karonova
- Federal Almazov North-West Medical Research Centre, 2 Akkuratova str., St. Petersburg, 197341, Russian Federation; Pavlov First Saint Petersburg State Medical University, 6-8L.Tolstoy str., St. Petersburg, 197022, Russian Federation.
| | - O Belyaeva
- Pavlov First Saint Petersburg State Medical University, 6-8L.Tolstoy str., St. Petersburg, 197022, Russian Federation.
| | - E B Jude
- Tameside Hospital NHS Foundation Trust, Ashton Under Lyne, OL69RW, UK.
| | - A Tsiberkin
- Federal Almazov North-West Medical Research Centre, 2 Akkuratova str., St. Petersburg, 197341, Russian Federation.
| | - A Andreeva
- Federal Almazov North-West Medical Research Centre, 2 Akkuratova str., St. Petersburg, 197341, Russian Federation.
| | - E Grineva
- Federal Almazov North-West Medical Research Centre, 2 Akkuratova str., St. Petersburg, 197341, Russian Federation; Pavlov First Saint Petersburg State Medical University, 6-8L.Tolstoy str., St. Petersburg, 197022, Russian Federation.
| | - P Pludowski
- Department of Biochemistry, Radioimmunology and Experimental Medicine, The Children's Memorial Health Institute, 04-730, Aleja Dzieci Polskich 20 str., Warsaw, Poland.
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Sharma DL, Lakhani HV, Klug RL, Snoad B, El-Hamdani R, Shapiro JI, Sodhi K. Investigating Molecular Connections of Non-alcoholic Fatty Liver Disease with Associated Pathological Conditions in West Virginia for Biomarker Analysis. ACTA ACUST UNITED AC 2017; 8. [PMID: 29177105 PMCID: PMC5701750 DOI: 10.4172/2155-9899.1000523] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a disease characterized by a steatosis of the liver that may progress to more serious pathological conditions including: nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. As the prevalence of NAFLD has increased worldwide in recent years, pathophysiology and risk factors associated with disease progression of NAFLD are at the focus of many studies. NAFLD is related to and shares common serum biomarkers with cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), obesity, and metabolic syndrome (MetS). West Virginia (WV) is a state with some of the highest rates of CVD, obesity and diabetes mellitus. As NAFLD is closely related to these diseases, it is of particular interest in WV. Currently there is no cost-effective, standardized method used clinically to detect NAFLD prior to the onset of reversible complications. At this time, the diagnosis of NAFLD is made with costly radiologic studies and invasive biopsy. These studies are only diagnostic once changes to hepatic tissue have occurred. The diagnosis of NAFLD by traditional methods may not allow for successful intervention and may not be readily available in areas with already sparse medical resources. In this literature review, we identify a list of biomarkers common among CVD, T2DM, obesity, MetS and NAFLD. From this research we propose the following biomarkers are good candidates for inclusion in a panel of biomarkers for the early detection of NAFLD: adiponectin, AST, ALT, apo-B, CK18, CPS1, CRP, FABP-1, ferritin, GGT, GRP78, HDL-C, IGF-1, IL-1β, 6, 8, 10, IRS-2PAI-1, leptin, lumican, MDA SREBP-1c and TNF-α. Creating and implementing a biomarker panel for the early detection and attenuation of NAFLD, prior to the onset of irreversible complication would provide maximum benefit and decrease the disease burden on the patients and healthcare system of WV.
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Affiliation(s)
- Dana L Sharma
- Department of Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA
| | - Hari Vishal Lakhani
- Department of Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA
| | - Rebecca L Klug
- Department of Surgery, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA
| | - Brian Snoad
- Department of Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA
| | - Rawan El-Hamdani
- Department of Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA
| | - Joseph I Shapiro
- Department of Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA
| | - Komal Sodhi
- Department of Surgery, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA
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14
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Orchard TJ, Cariou B, Connelly MA, Otvos JD, Zhang S, Antalis CJ, Ivanyi T, Hoogwerf BJ. The effects of basal insulin peglispro vs. insulin glargine on lipoprotein particles by NMR and liver fat content by MRI in patients with diabetes. Cardiovasc Diabetol 2017; 16:73. [PMID: 28587667 PMCID: PMC5461740 DOI: 10.1186/s12933-017-0555-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Accepted: 05/26/2017] [Indexed: 12/23/2022] Open
Abstract
Background In Phase 2/3 studies of basal insulin peglispro (BIL) compared to insulin glargine, patients with type 1 or type 2 diabetes previously treated with insulin and randomized to BIL had an increase in serum triglycerides (TGs). To further understand lipoprotein changes, a lipid substudy which included liver fat content was designed to assess relationships among the measured variables for each diabetes cohort and compare the hepato-preferential insulin BIL to glargine. Methods In three cohorts of patients with diabetes (type 1, type 2 insulin naïve, and type 2 previously on insulin; n = 652), liver fat content (LFC) was determined by magnetic resonance imaging (MRI) and blood lipids were analyzed by nuclear magnetic resonance (NMR) spectroscopy at baseline, 26 and 52 weeks of treatment. Apolipoproteins, adiponectin, and other lipid parameters were also measured. Descriptive statistics were done, as well as correlation analyses to look for relationships among LFC and lipoproteins or other lipid measures. Results In patients with type 1 diabetes treated with BIL, but not glargine, small LDL and medium and large VLDL subclass concentrations increased from baseline. In patients with type 2 diabetes previously on insulin and treated with BIL, large VLDL concentration increased from baseline. In insulin naïve patients with type 2 diabetes treated with BIL, there were very few changes, while in those treated with glargine, small LDL and large VLDL decreased from baseline. Baseline LFC correlated significantly in one or more cohorts with baseline large VLDL, small LDL, VLDL size, and Apo C3. Changes in LFC by treatment showed generally weak correlations with lipoprotein changes, except for positive correlations with large VLDL and VLDL size. Adiponectin was higher in patients with type 1 diabetes compared to patients with type 2 diabetes, but decreased with treatment with both BIL and glargine. Conclusions The lipoprotein changes were in line with the observed changes in serum TGs; i.e., the cohorts experiencing increased TGs and LFC with BIL treatment had decreased LDL size and increased VLDL size. These data and analyses add to the currently available information on the metabolic effects of insulins in a very carefully characterized cohort of patients with diabetes. Clinicaltrials.gov registration numbers and dates NCT01481779 (2011), NCT01435616 (2011), NCT01454284 (2011), NCT01582451 (2012) Electronic supplementary material The online version of this article (doi:10.1186/s12933-017-0555-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Trevor J Orchard
- Department of Epidemiology, GSPH, University of Pittsburgh, Pittsburgh, PA, USA
| | - Bertrand Cariou
- l'Institut du Thorax, CHU Nantes INSERM, CNRS, UNIV Nantes, Nantes, France
| | - Margery A Connelly
- LipoScience, Laboratory Corporation of America Holdings, Morrisville, NC, 27560, USA
| | - James D Otvos
- LipoScience, Laboratory Corporation of America Holdings, Morrisville, NC, 27560, USA
| | - Shuyu Zhang
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, 46285, USA
| | - Caryl J Antalis
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, 46285, USA
| | | | - Byron J Hoogwerf
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, 46285, USA.
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15
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Targher G, Rossini M, Lonardo A. Evidence that non-alcoholic fatty liver disease and polycystic ovary syndrome are associated by necessity rather than chance: a novel hepato-ovarian axis? Endocrine 2016; 51:211-221. [PMID: 26024975 DOI: 10.1007/s12020-015-0640-8] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Accepted: 05/22/2015] [Indexed: 02/06/2023]
Abstract
Increasing evidence suggests that non-alcoholic fatty liver disease (NAFLD) and polycystic ovary syndrome (PCOS) are associated with obesity, insulin resistance, metabolic syndrome, cardiovascular disease, cirrhosis, and liver tumors. On these grounds, we have hypothesized that NAFLD and PCOS occur more frequently than expected by chance alone. We have tested this hypothesis by reviewing the clinical and biological evidence that supports a significant association between NAFLD and PCOS. PubMed was extensively searched for articles published through March 2015 using the keywords "nonalcoholic fatty liver disease" or "fatty liver" combined with "PCOS." Several cross-sectional and case-control studies have consistently demonstrated that the prevalence of NAFLD is remarkably increased in young women with PCOS, independent of overweight/obesity and other coexisting metabolic syndrome features, and that these women are more likely to have the more severe forms of NAFLD (non-alcoholic steatohepatitis, advanced fibrosis, and cirrhosis). Accumulating evidence suggests that NAFLD, especially its necro-inflammatory form, may exacerbate hepatic and systemic insulin resistance and releases multiple pro-inflammatory, pro-coagulant, and pro-fibrogenic mediators that may play important roles in the pathophysiology of PCOS. These findings call for more active and systematic search for NAFLD among women with PCOS. Conversely, gastroenterologists/hepatologists need to be aware of the presence of PCOS among female patients with NAFLD and compatible clinical features. Finally, all these patients should undergo regular follow-up not only for liver-related complications but also for cardio-metabolic diseases.
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Affiliation(s)
- Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Piazzale Stefani, 1, 37126, Verona, Italy.
| | - Maurizio Rossini
- Section of Rheumatology, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Amedeo Lonardo
- Outpatient Liver Clinic and Division of Internal Medicine - Department of Biomedical, Metabolic and Neural Sciences, NOCSAE, Baggiovara, Azienda USL, University of Modena and Reggio Emilia, Modena, Italy
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16
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Liu D, Li S, Li Z. Adiponectin: A biomarker for chronic hepatitis C? Cytokine 2015; 89:27-33. [PMID: 26683021 DOI: 10.1016/j.cyto.2015.10.016] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Revised: 10/30/2015] [Accepted: 10/30/2015] [Indexed: 12/14/2022]
Abstract
Adiponectin, a hormone primarily synthesized and secreted by adipose tissue, plays a pivotal role in lipid metabolism. Chronic hepatitis C (CHC) infection is characterized by disordered lipid metabolism, which may potentially evolve into steatosis over a period of time. A growing body of evidence appears to link decreased adiponectin plasma levels with severe CHC-related steatosis, which suggests a potential role of this adipokine as a diagnostic and therapeutic target for clinical application. In this review, we have attempted to summarize the current status of adiponectin research in the context of CHC, concentrating predominantly on its roles in CHC, and its potential relevance as a biomarker for CHC.
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Affiliation(s)
- Ding Liu
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Shengyu Li
- Department of General Surgery, The Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Zhihong Li
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
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17
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Lee SK, Yoon DW, Lee SW, Kim JY, Kim JK, Shin C. Non-alcoholic fatty liver disease among sasang constitutional types: a population-based study in Korea. Altern Ther Health Med 2015; 15:399. [PMID: 26547840 PMCID: PMC4637136 DOI: 10.1186/s12906-015-0925-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Accepted: 11/02/2015] [Indexed: 12/14/2022]
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and is highly prevalent in populations with metabolic conditions such as obesity and type II diabetes. Specific types of Sasang constitution can act as a risk factor for metabolic diseases, but there are no studies addressing the association between the Sasang constitutional types (SCTs) and NAFLD. Methods A total of 1184 individuals (508 males, 676 females) that enrolled in the Korean Genome and Epidemiology Study were included in the present study. Classification of SCTs was done with an integrated diagnostic model. NAFLD was diagnosed when the liver attenuation index (LAI) value was <5 Hounsfield units using computed tomography. Relationships between the SCTs and NAFLD were analyzed using multiple logistic regressions. Results The average LAI was 13.3 ± 6.0 in the So-eum (SE) type, 12.3 ± 7.0 in the So-yang (SY) type, and 6.5 ± 9.9 in the Tae-eum (TE) type. Prevalence of NAFLD was 4.7 % in the SE type, 14.0 % in the SY type, and 34 % in the TE type. Even after adjusting for possible confounders, the SY and TE types continued to show a 3.90-fold (95 % CI, 1.60-9.51; P = 0.0028) and 3.36-fold (95 % CI, 1.42-7.92; P = 0.0057) increase in chance of having NAFLD, respectively, compared with the SE type. In the additional analysis including only non-obese subjects, the odds ratio of NAFLD was 3.27 (95 % CI, 1.29-8.29; P = 0.0126) in the SY type and 3.53 (95 % CI, 1.30-9.58; P = 0.0134) in the TE type compared with SE type. In the multivariate analysis to determine which parameter had an independent association with NAFLD, higher body mass index, alanine aminotransferase (ALT), triglyceride (TG), and low high-density lipoprotein cholesterol were independently associated with developing NAFLD in the SY type. In contrast, male sex, alcohol consumption, higher ALT, TG, and fasting glucose were risk factors for NAFLD in the TE type. Conclusions These results indicated that the SY and TE types are independent risk factors for NAFLD.
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Ahmed MH, Husain NEO, Almobarak AO. Nonalcoholic Fatty liver disease and risk of diabetes and cardiovascular disease: what is important for primary care physicians? J Family Med Prim Care 2015; 4:45-52. [PMID: 25810989 PMCID: PMC4367006 DOI: 10.4103/2249-4863.152252] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is emerging as the most common chronic liver condition in Western World and across the globe. NAFLD prevalence is estimated to be around one-third of the total population. There are no published data that project the future prevalence of NAFLD, but with an increase in epidemic of diabetes and obesity, it is possible to suggest an increase in a number of individuals with NAFLD. NAFLD is associated with insulin resistance and occurs with an increase in cluster of features of metabolic syndrome and type 2 diabetes. Therefore, it is important to exclude the possibility of diabetes in those individuals with evidence of fatty liver. The global diabetes epidemic continues to grow, and it is estimated that the number of people with diabetes will double by year 2030. NAFLD is also a risk factor for an increase in cardiovascular incidence independent of age, sex, low-density lipoprotein-cholesterol, smoking, and cluster of metabolic syndromes. It is expected that NAFLD will be an important challenge for health providers in the near future. Taking all these factors into consideration, we believe that increasing awareness of metabolic and cardiovascular impact of NAFLD among general practitioners and health authorities may decrease the serious consequences of late diagnosis of NAFLD. Importantly, the collaboration between medical specialties is vital in decreasing the impact of the epidemic of NAFLD. The focus of this review is in the role of primary care physician in diagnosis, treatment and prevention of NAFLD and patients education.
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Affiliation(s)
- Mohamed H Ahmed
- Department of Medicine, Milton Keynes Hospital NHS Foundation Trust, Eaglestone, Milton Keynes, Buckinghamshire, UK
| | - Nazik Elmalaika Os Husain
- Department of Pathology, Faculty of Medicine and Health Sciences, Omdurman Islamic University, Khartoum, Sudan
| | - Ahmed O Almobarak
- Department of Pathology, Faculty of Medicine, University of Medical Sciences and Technology, Khartoum, Sudan
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Peta V, Torti C, Milic N, Focà A, Abenavoli L. Adiponectin serum level in chronic hepatitis C infection and therapeutic profile. World J Hepatol 2015; 7:44-52. [PMID: 25624996 PMCID: PMC4295193 DOI: 10.4254/wjh.v7.i1.44] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2014] [Revised: 07/20/2014] [Accepted: 11/19/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatic steatosis is commonly seen in the patients with chronic hepatitis C virus (HCV) infection. HCV is closely associated with lipid metabolism, and viral steatosis is more common in genotype 3 infection owing to a direct cytopathic effect of HCV core protein. In non-genotype 3 infection, hepatic steatosis is considered largely to be the result of the alterations in host metabolism; metabolic steatosis is primarily linked with HCV genotype 1. Adipose tissue secretes different hormones involved in glucose and lipid metabolisms. It has been demonstrated that adipocytokines are involved in the pathogenesis of non-alcoholic fatty liver disease, as the decreased plasma adiponectin levels, a soluble matrix protein expressed by adipoctyes and hepatocyte, are associated with liver steatosis. Various studies have shown that steatosis is strongly correlated negatively with adiponectin in the patients with HCV infection. The role of adiponectin in hepatitis C virus induced steatosis is still not completely understood, but the relationship between adiponectin low levels and liver steatosis is probably due to the ability of adiponectin to protect hepatocytes from triglyceride accumulation by increasing β-oxidation of free fatty acid and thus decreasing de novo free fatty acid production.
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20
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Fisher L, Srikusalanukul W, Fisher A, Smith P. Liver function parameters in hip fracture patients: relations to age, adipokines, comorbidities and outcomes. Int J Med Sci 2015; 12:100-15. [PMID: 25589886 PMCID: PMC4293175 DOI: 10.7150/ijms.10696] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2014] [Accepted: 04/11/2014] [Indexed: 02/07/2023] Open
Abstract
AIM To asses liver markers in older patients with hip fracture (HF) in relation to age, comorbidities, metabolic characteristics and short-term outcomes. METHODS In 294 patients with HF (mean age 82.0±7.9 years, 72.1% women) serum alanine aminotransferase (ALT), gammaglutamyltransferase (GGT), alkaline phosphatase (ALP), albumin, bilirubin, 25(OH)vitaminD, PTH, calcium, phosphate, magnesium, adiponectin, leptin, resistin, thyroid function and cardiac troponin I were measured. RESULTS Elevated ALT, GGT, ALP or bilirubin levels on admission were observed in 1.7%-9.9% of patients. With age GGT, ALT and leptin decrease, while PTH and adiponectin concentrations increase. Higher GGT (>30 U/L, median level) was associated with coronary artery disease (CAD), diabetes mellitus (DM), and alcohol overuse; lower ALT (≤20 U/L, median level) with dementia; total bilirubin>20 μmol/L with CAD and alcohol overuse; and albumin>33 g/L with CAD. Multivariate adjusted regression analyses revealed ALT, ALP, adiponectin, alcohol overuse and DM as independent and significant determinants of GGT (as continuous or categorical variable); GGT for each other liver marker; and PTH for adiponectin. The risk of prolonged hospital stay (>20 days) was about two times higher in patients with GGT>30 U/L or adiponectin>17.14 ng/L (median level) and 4.7 times higher if both conditions coexisted. The risk of in-hospital death was 3 times higher if albumin was <33 g/L. CONCLUSIONS In older HF patients liver markers even within the normal range are associated with age-related disorders and outcomes. Adiponectin (but not 25(OH)vitaminD, PTH, leptin or resistin) is an independent contributor to higher GGT. Serum GGT and albumin predict prolonged hospital stay and in-hospital death, respectively. A unifying hypothesis of the findings presented.
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Affiliation(s)
- Leon Fisher
- 1. Department of Gastroenterology, The Canberra Hospital, Canberra, ACT, Australia
| | - Wichat Srikusalanukul
- 2. Department of Geriatric Medicine, The Canberra Hospital, Canberra, ACT, Australia
| | - Alexander Fisher
- 2. Department of Geriatric Medicine, The Canberra Hospital, Canberra, ACT, Australia ; 4. Australian National University Medical School, Canberra, ACT, Australia
| | - Paul Smith
- 3. Department of Orthopaedic Surgery, The Canberra Hospital, Canberra, ACT, Australia ; 4. Australian National University Medical School, Canberra, ACT, Australia
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Ma H, Cui F, Dong JJ, You GP, Yang XJ, Lu HD, Huang YL. Therapeutic effects of globular adiponectin in diabetic rats with nonalcoholic fatty liver disease. World J Gastroenterol 2014; 20:14950-14957. [PMID: 25356056 PMCID: PMC4209559 DOI: 10.3748/wjg.v20.i40.14950] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2013] [Revised: 02/14/2014] [Accepted: 06/13/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the therapeutic role of globular adiponectin (gAd) in high-fat diet/streptozotocin (STZ)-induced type 2 diabetic rats with nonalcoholic fatty liver disease (NAFLD).
METHODS: Seven rats were fed a basic diet (normal control group; NC) during the experiment. Experimental rats (14 rats) were given a high-fat diet for 4 wk and were then injected with STZ to induce type 2 diabetes mellitus (T2DM) and NAFLD. Half of the T2DM/NAFLD rats were randomly injected intraperitoneally with gAd for 7 d (gAd-treated group), while the other 7 rats (T2DM/NAFLD group) received 0.9% saline. Plasma biochemical parameters and insulin concentrations were measured. Liver histopathology was examined by hematoxylin-eosin staining. Insulin receptor expression in the liver was analyzed by immunohistochemical staining, Western blot and quantitative real-time reverse transcription polymerase chain reaction analysis.
RESULTS: Compared to the control group, the T2DM/NAFLD group had increased levels of glucolipid and decreased levels of insulin. Plasma glucose and lipid levels were decreased in the gAd-treated group, while serum insulin levels increased. The expression of insulin receptor in the T2DM/NAFLD group increased compared with the NC group, and gAd downregulated insulin receptor expression in the livers of T2DM/NAFLD rats. Steatosis of the liver was alleviated in the gAd-treated group compared to the T2DM/NAFLD group (NAS 1.39 ± 0.51 vs 1.92 ± 0.51, P < 0.05).
CONCLUSION: Globular adiponectin exerts beneficial effects in T2DM rats with NAFLD by promoting insulin secretion, mediating glucolipid metabolism, regulating insulin receptor expression and alleviating hepatic steatosis.
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MESH Headings
- Adiponectin/administration & dosage
- Adiponectin/pharmacology
- Animals
- Biomarkers/blood
- Blood Glucose/metabolism
- Diabetes Mellitus, Experimental/blood
- Diabetes Mellitus, Experimental/chemically induced
- Diabetes Mellitus, Experimental/drug therapy
- Diabetes Mellitus, Experimental/genetics
- Diabetes Mellitus, Type 2/blood
- Diabetes Mellitus, Type 2/chemically induced
- Diabetes Mellitus, Type 2/drug therapy
- Diabetes Mellitus, Type 2/genetics
- Diet, High-Fat
- Hypoglycemic Agents/administration & dosage
- Hypoglycemic Agents/pharmacology
- Injections, Intraperitoneal
- Insulin/blood
- Lipids/blood
- Liver/drug effects
- Liver/metabolism
- Liver/pathology
- Male
- Non-alcoholic Fatty Liver Disease/blood
- Non-alcoholic Fatty Liver Disease/drug therapy
- Non-alcoholic Fatty Liver Disease/etiology
- Non-alcoholic Fatty Liver Disease/genetics
- Non-alcoholic Fatty Liver Disease/pathology
- RNA, Messenger/metabolism
- Rats, Wistar
- Receptor, Insulin/drug effects
- Receptor, Insulin/genetics
- Receptor, Insulin/metabolism
- Streptozocin
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22
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Abd El-Kader SM, Al-Jiffri OH, Al-Shreef FM. Markers of liver function and inflammatory cytokines modulation by aerobic versus resisted exercise training for nonalcoholic steatohepatitis patients. Afr Health Sci 2014; 14:551-7. [PMID: 25352871 DOI: 10.4314/ahs.v14i3.8] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Non-alcoholic steatohepatitis is a growing public health problem with no approved therapy; as cytokines and other pro-inflammatory mediators may each play a role in transition of steatosis to NASH which is projected to be the leading cause of liver transplantation in the United States by 2020. OBJECTIVE The aim of this study was to compare the impact of aerobic versus resisted exercise training on inflammatory cytokines and markers of liver function in patients with nonalcoholic steatohepatitis. MATERIAL AND METHODS Fifty patients with NASH were included in the study and divided into two subgroups. Participants were included into 2 equal groups; the first group (A) received aerobic exercise training. The second group (B) received resisted exercise training three times a week for 3 months. RESULTS The mean values of TNF- α, IL6, IL8, ALT and AST were significantly decreased in group (A) and group (B). Also; there was a significant difference between both groups after treatment. CONCLUSION Aerobic exercise training modulates inflammatory cytokine levels and markers of liver function in patients with nonalcoholic steatohepatitis.
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Affiliation(s)
- Shehab M Abd El-Kader
- Department of Physical Therapy, Faculty of Applied Medical Sciences, King Abdulaziz University
| | - Osama H Al-Jiffri
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University
| | - Fadwa M Al-Shreef
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University
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23
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Brockman DA, Chen X, Gallaher DD. High-viscosity dietary fibers reduce adiposity and decrease hepatic steatosis in rats fed a high-fat diet. J Nutr 2014; 144:1415-22. [PMID: 24991042 DOI: 10.3945/jn.114.191577] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Viscous dietary fiber consumption lowers the postprandial glucose curve and may decrease obesity and associated comorbidities such as insulin resistance and fatty liver. We determined the effect of 2 viscous fibers, one fermentable and one not, on the development of adiposity, fatty liver, and metabolic flexibility in a model of diet-induced obesity. Rats were fed a normal-fat (NF) diet (26% energy from fat), a high-fat diet (60% energy from fat), each containing 5% fiber as cellulose (CL; nonviscous and nonfermentable), or 5% of 1 of 2 highly viscous fibers-hydroxypropyl methylcellulose (HPMC; nonfermentable) or guar gum (GG; fermentable). After 10 wk, fat mass percentage in the NF (18.0%; P = 0.03) and GG groups (17.0%; P < 0.01) was lower than the CL group (20.7%). The epididymal fat pad weight of the NF (3.9 g; P = 0.04), HPMC (3.9 g; P = 0.03), and GG groups (3.6 g; P < 0.01) was also lower than the CL group (5.0 g). The HPMC (0.11 g/g liver) and GG (0.092 g/g liver) groups had lower liver lipid concentrations compared with the CL group (0.14 g/g liver). Fat mass percentage, epididymal fat pad weight, and liver lipid concentration were not different among the NF, HPMC, and GG groups. The respiratory quotient was higher during the transition from the diet-deprived to fed state in the GG group (P = 0.002) and tended to be higher in the HPMC group (P = 0.06) compared with the CL group, suggesting a quicker shift from fatty acid (FA) to carbohydrate oxidation. The HPMC group [15.1 nmol/(mg ⋅ h)] had higher ex vivo palmitate oxidation in muscle compared with the GG [11.7 nmol/(mg ⋅ h); P = 0.04] and CL groups [10.8 nmol/(mg ⋅ h); P < 0.01], implying a higher capacity to oxidize FAs. Viscous fibers can reduce the adiposity and hepatic steatosis that accompany a high-fat diet, and increase metabolic flexibility, regardless of fermentability.
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Affiliation(s)
- David A Brockman
- Department of Food Science and Nutrition, University of Minnesota, St. Paul, MN
| | - Xiaoli Chen
- Department of Food Science and Nutrition, University of Minnesota, St. Paul, MN
| | - Daniel D Gallaher
- Department of Food Science and Nutrition, University of Minnesota, St. Paul, MN
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24
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Milić S, Lulić D, Štimac D. Non-alcoholic fatty liver disease and obesity: Biochemical, metabolic and clinical presentations. World J Gastroenterol 2014; 20:9330-9337. [PMID: 25071327 PMCID: PMC4110564 DOI: 10.3748/wjg.v20.i28.9330] [Citation(s) in RCA: 263] [Impact Index Per Article: 23.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 01/26/2014] [Accepted: 03/19/2014] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. Presentation of the disease ranges from simple steatosis to non-alcoholic steatohepatitis (NASH). NAFLD is a hepatic manifestation of metabolic syndrome that includes central abdominal obesity along with other components. Up to 80% of patients with NAFLD are obese, defined as a body mass index (BMI) > 30 kg/m2. However, the distribution of fat tissue plays a greater role in insulin resistance than the BMI. The large amount of visceral adipose tissue (VAT) in morbidly obese (BMI > 40 kg/m2) individuals contributes to a high prevalence of NAFLD. Free fatty acids derived from VAT tissue, as well as from dietary sources and de novo lipogenesis, are released to the portal venous system. Excess free fatty acids and chronic low-grade inflammation from VAT are considered to be two of the most important factors contributing to liver injury progression in NAFLD. In addition, secretion of adipokines from VAT as well as lipid accumulation in the liver further promotes inflammation through nuclear factor kappa B signaling pathways, which are also activated by free fatty acids, and contribute to insulin resistance. Most NAFLD patients are asymptomatic on clinical presentation, even though some may present with fatigue, dyspepsia, dull pain in the liver and hepatosplenomegaly. Treatment for NAFLD and NASH involves weight reduction through lifestyle modifications, anti-obesity medication and bariatric surgery. This article reviews the available information on the biochemical and metabolic phenotypes associated with obesity and fatty liver disease. The relative contribution of visceral and liver fat to insulin resistance is discussed, and recommendations for clinical evaluation of affected individuals is provided.
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25
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Jung UJ, Choi MS. Obesity and its metabolic complications: the role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease. Int J Mol Sci 2014; 15:6184-223. [PMID: 24733068 PMCID: PMC4013623 DOI: 10.3390/ijms15046184] [Citation(s) in RCA: 1298] [Impact Index Per Article: 118.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Revised: 03/27/2014] [Accepted: 04/01/2014] [Indexed: 02/06/2023] Open
Abstract
Accumulating evidence indicates that obesity is closely associated with an increased risk of metabolic diseases such as insulin resistance, type 2 diabetes, dyslipidemia and nonalcoholic fatty liver disease. Obesity results from an imbalance between food intake and energy expenditure, which leads to an excessive accumulation of adipose tissue. Adipose tissue is now recognized not only as a main site of storage of excess energy derived from food intake but also as an endocrine organ. The expansion of adipose tissue produces a number of bioactive substances, known as adipocytokines or adipokines, which trigger chronic low-grade inflammation and interact with a range of processes in many different organs. Although the precise mechanisms are still unclear, dysregulated production or secretion of these adipokines caused by excess adipose tissue and adipose tissue dysfunction can contribute to the development of obesity-related metabolic diseases. In this review, we focus on the role of several adipokines associated with obesity and the potential impact on obesity-related metabolic diseases. Multiple lines evidence provides valuable insights into the roles of adipokines in the development of obesity and its metabolic complications. Further research is still required to fully understand the mechanisms underlying the metabolic actions of a few newly identified adipokines.
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Affiliation(s)
- Un Ju Jung
- Center for Food and Nutritional Genomics Research, Kyungpook National University, 1370 Sankyuk Dong Puk-ku, Daegu 702-701, Korea.
| | - Myung-Sook Choi
- Center for Food and Nutritional Genomics Research, Kyungpook National University, 1370 Sankyuk Dong Puk-ku, Daegu 702-701, Korea.
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26
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Silva TE, Colombo G, Schiavon LL. Adiponectin: A multitasking player in the field of liver diseases. DIABETES & METABOLISM 2014; 40:95-107. [PMID: 24486145 DOI: 10.1016/j.diabet.2013.11.004] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Revised: 11/19/2013] [Accepted: 11/21/2013] [Indexed: 12/18/2022]
Abstract
Adiponectin is the most abundant adipokine synthesized by adipose tissue and has been shown to be a key component in the relationship between adiposity, insulin resistance and inflammation. It circulates in plasma at physiological concentrations that represent 0.05% of all plasma proteins. Adiponectin has trimeric, hexameric and multimeric forms that bind to receptors AdipoR1, AdipoR2 and T-cadherin especially in liver, muscle and endothelial cells. Adiponectin is considered a potent modulator of lipid and glucose metabolism with antidiabetic, antiatherogenic and anti-inflammatory properties, and plays an important role in the pathogenesis of metabolic diseases. The hepatoprotective effects of adiponectin, especially in non-alcoholic fatty liver disease (NAFLD), have been widely investigated, and its antisteatotic, anti-inflammatory and antifibrogenic effects have already been described. Adiponectin levels are reduced in individuals with fatty liver disease independently of body mass index, insulin resistance and other adipokines, and are inversely related to the severity of steatosis and necroinflammation, suggesting an important role in the relationship between adipose tissue, the liver and insulin sensitivity. Adiponectin has also been found to be reduced in cases of hepatitis B and C infection, and in cholestatic and autoimmune diseases, but is increased in patients with cirrhosis of different aetiologies. In addition, an important role for the liver in the regulation of adiponectin secretion by adipocytes, mediated by bile acids, has recently been proposed. The present report describes the importance of adiponectin in hepatic diseases as well as some future perspectives of the role of adiponectin as a biomarker and therapeutic target in liver diseases.
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Affiliation(s)
- T E Silva
- Division of Gastroenterology, Federal University of Santa Catarina Campus, Universitário Reitor João David Ferreira Lima, Trindade Florianópolis, SC, Brazil 88040970.
| | - G Colombo
- Division of Gastroenterology, Federal University of Santa Catarina Campus, Universitário Reitor João David Ferreira Lima, Trindade Florianópolis, SC, Brazil 88040970
| | - L L Schiavon
- Division of Gastroenterology, Federal University of Santa Catarina Campus, Universitário Reitor João David Ferreira Lima, Trindade Florianópolis, SC, Brazil 88040970
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27
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Pan MH, Lai CS, Tsai ML, Ho CT. Chemoprevention of nonalcoholic fatty liver disease by dietary natural compounds. Mol Nutr Food Res 2013; 58:147-71. [PMID: 24302567 DOI: 10.1002/mnfr.201300522] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2013] [Revised: 09/25/2013] [Accepted: 10/09/2013] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) refers to a wide spectrum of liver disease that is not from excess alcohol consumption, but is often associated with obesity, type 2 diabetes, and metabolic syndrome. NAFLD pathogenesis is complicated and involves oxidative stress, lipotoxicity, mitochondrial damage, insulin resistance, inflammation, and excessive dietary fat intake, which increase hepatic lipid influx and de novo lipogenesis and impair insulin signaling, thus promoting hepatic triglyceride accumulation and ultimately NAFLD. Overproduction of proinflammatory adipokines from adipose tissue also affects hepatic metabolic function. Current NAFLD therapies are limited; thus, much attention has been focused on identification of potential dietary substances from fruits, vegetables, and edible plants to provide a new strategy for NAFLD treatment. Dietary natural compounds, such as carotenoids, omega-3-PUFAs, flavonoids, isothiocyanates, terpenoids, curcumin, and resveratrol, act through a variety of mechanisms to prevent and improve NAFLD. Here, we summarize and briefly discuss the currently known targets and signaling pathways as well as the role of dietary natural compounds that interfere with NAFLD pathogenesis.
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Affiliation(s)
- Min-Hsiung Pan
- Institute of Food Science and Technology, National Taiwan University, Taipei, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
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28
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Predictive value of the adiponectin to leptin ratio for diagnosis of steatohepatitis in patients with nonalcoholic fatty liver disease. EGYPTIAN LIVER JOURNAL 2013. [DOI: 10.1097/01.elx.0000427107.63804.34] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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29
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Mazaki-Tovi M, Abood S, Segev G, Schenck P. Alterations in Adipokines in Feline Hepatic Lipidosis. J Vet Intern Med 2013; 27:242-9. [DOI: 10.1111/jvim.12055] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2012] [Revised: 12/18/2012] [Accepted: 01/21/2013] [Indexed: 12/31/2022] Open
Affiliation(s)
- M. Mazaki-Tovi
- Department of Pathobiology and Diagnostic Investigation; Diagnostic Center for Population and Animal Health; East Lansing MI
| | - S.K. Abood
- Department of Small Animal Clinical Sciences; College of Veterinary Medicine; Michigan State University; East Lansing MI
| | - G. Segev
- Koret School of Veterinary Medicine; The Hebrew University of Jerusalem; Rehovot Israel
| | - P.A. Schenck
- Department of Pathobiology and Diagnostic Investigation; Diagnostic Center for Population and Animal Health; East Lansing MI
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30
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Meyer BJ, Stewart FM, Brown EA, Cooney J, Nilsson S, Olivecrona G, Ramsay JE, Griffin BA, Caslake MJ, Freeman DJ. Maternal obesity is associated with the formation of small dense LDL and hypoadiponectinemia in the third trimester. J Clin Endocrinol Metab 2013; 98:643-52. [PMID: 23337718 PMCID: PMC3736085 DOI: 10.1210/jc.2012-3481] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
CONTEXT Maternal obesity is associated with high plasma triglyceride, poor vascular function, and an increased risk for pregnancy complications. In normal-weight pregnant women, higher triglyceride is associated with increased small, dense low-density lipoprotein (LDL). HYPOTHESIS In obese pregnancy, increased plasma triglyceride concentrations result in triglyceride enrichment of very low-density lipoprotein-1 particles and formation of small dense LDL via lipoprotein lipase. DESIGN Women (n = 55) of body mass index of 18-46 kg/m(2) were sampled longitudinally at 12, 26, and 35 weeks' gestation and 4 months postnatally. SETTING Women were recruited at hospital antenatal appointments, and study visits were in a clinical research suite. OUTCOME MEASURES Plasma concentrations of lipids, triglyceride-rich lipoproteins, lipoprotein lipase mass, estradiol, steroid hormone binding globulin, insulin, glucose, leptin, and adiponectin were determined. RESULTS Obese women commenced pregnancy with higher plasma triglyceride, reached the same maximum, and then returned to higher postnatal levels than normal-weight women. Estradiol response to pregnancy (trimester 1-3 incremental area under the curve) was positively associated with plasma triglyceride response (r(2) adjusted 25%, P < .001). In the third trimester, the proportion of small, dense LDL was 2-fold higher in obese women than normal-weight women [mean (SD) 40.7 (18.8) vs 21.9 (10.9)%, P = .014], and 35% of obese, 14% of overweight, and none of the normal-weight women displayed an atherogenic LDL subfraction phenotype. The small, dense LDL mass response to pregnancy was inversely associated with adiponectin response (17%, P = .013). CONCLUSIONS Maternal obesity is associated with an atherogenic LDL subfraction phenotype and may provide a mechanistic link to poor vascular function and adverse pregnancy outcome.
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Affiliation(s)
- Barbara J Meyer
- Metabolic Research Centre, School of Health Sciences, University of Wollongong, Wollongong, New South Wales 2500, Australia
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31
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Brockman DA, Chen X, Gallaher DD. Consumption of a high β-glucan barley flour improves glucose control and fatty liver and increases muscle acylcarnitines in the Zucker diabetic fatty rat. Eur J Nutr 2012. [PMID: 23229409 DOI: 10.1007/s00394‐012‐0478‐2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
PURPOSE The soluble fiber β-glucan, a natural component of barley, has been shown to lower the postprandial glucose response and is thought to improve insulin resistance. METHODS This study examined the effect of chronic consumption of the high β-glucan barley flour on glucose control, liver lipids and markers of muscle fatty acid oxidation in the Zucker diabetic fatty (ZDF) rat. Two groups of ZDF rats were fed diets containing either 6% β-glucan in the form of barley flour or cellulose as a control for 6 weeks. A group of Zucker lean rats served as a negative control. RESULTS The barley flour group had an increased small intestinal contents viscosity compared to the obese control group. After 6 weeks, the barley flour group had reduced glycated hemoglobin, lower relative kidney weights and a reduced area under the curve during a glucose tolerance test, indicating improved glucose control. Fasting plasma adiponectin levels increased in the barley flour group and were not different than the lean control group. ZDF rats on the barley flour diet had lower relative epididymal fat pad weights than the obese control and a greater food efficiency ratio. The barley flour group also had reduced liver weights and a decreased concentration of liver lipids. The barley flour group had significantly higher concentrations of muscle acylcarnitines, a metabolite generated during fatty acid oxidation. CONCLUSION These results show that chronic consumption of β-glucans can improve glucose control and decrease fatty liver in a model of diabetes with obesity.
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Affiliation(s)
- David A Brockman
- Department of Food Science and Nutrition, University of Minnesota-Twin Cities, 1334 Eckles Avenue, St. Paul, MN, 55108-1038, USA
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Consumption of a high β-glucan barley flour improves glucose control and fatty liver and increases muscle acylcarnitines in the Zucker diabetic fatty rat. Eur J Nutr 2012; 52:1743-53. [PMID: 23229409 DOI: 10.1007/s00394-012-0478-2] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2012] [Accepted: 11/27/2012] [Indexed: 01/21/2023]
Abstract
PURPOSE The soluble fiber β-glucan, a natural component of barley, has been shown to lower the postprandial glucose response and is thought to improve insulin resistance. METHODS This study examined the effect of chronic consumption of the high β-glucan barley flour on glucose control, liver lipids and markers of muscle fatty acid oxidation in the Zucker diabetic fatty (ZDF) rat. Two groups of ZDF rats were fed diets containing either 6% β-glucan in the form of barley flour or cellulose as a control for 6 weeks. A group of Zucker lean rats served as a negative control. RESULTS The barley flour group had an increased small intestinal contents viscosity compared to the obese control group. After 6 weeks, the barley flour group had reduced glycated hemoglobin, lower relative kidney weights and a reduced area under the curve during a glucose tolerance test, indicating improved glucose control. Fasting plasma adiponectin levels increased in the barley flour group and were not different than the lean control group. ZDF rats on the barley flour diet had lower relative epididymal fat pad weights than the obese control and a greater food efficiency ratio. The barley flour group also had reduced liver weights and a decreased concentration of liver lipids. The barley flour group had significantly higher concentrations of muscle acylcarnitines, a metabolite generated during fatty acid oxidation. CONCLUSION These results show that chronic consumption of β-glucans can improve glucose control and decrease fatty liver in a model of diabetes with obesity.
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Brockman DA, Chen X, Gallaher DD. Hydroxypropyl methylcellulose, a viscous soluble fiber, reduces insulin resistance and decreases fatty liver in Zucker Diabetic Fatty rats. Nutr Metab (Lond) 2012; 9:100. [PMID: 23146593 PMCID: PMC3565887 DOI: 10.1186/1743-7075-9-100] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2012] [Accepted: 11/05/2012] [Indexed: 12/13/2022] Open
Abstract
Background Diets producing a high glycemic response result in exaggerated insulin secretion which induces hepatic lipogenesis, contributing to development of insulin resistance and fatty liver. Viscous dietary fibers blunt the postprandial rise in blood glucose, however their effect on type 2 diabetes and obesity are not entirely known. This study examined the effect of chronic consumption of the viscous, non-fermentable dietary fiber, hydroxypropyl methylcellulose (HPMC), on glucose control, insulin resistance and liver lipids in an obese diabetic rat model. Methods Three groups of Zucker Diabetic Fatty (ZDF) rats were fed diets containing either 5% non-viscous cellulose (control), low viscosity HPMC (LV-HPMC) or high viscosity HPMC (HV- HPMC) for six weeks. Zucker lean littermates consuming cellulose served as a negative control. Markers of glucose control, including oral glucose tolerance test, glycated hemoglobin and urinary glucose, were measured as well as adiposity and the accumulation of liver lipids. Results The HPMC diets increased the viscosity of the small intestinal contents and reduced the postprandial rise in blood glucose. The food efficiency ratio was greater with HPMC feeding compared to the obese control and urinary excretion of glucose and ketone bodies was reduced. The two HPMC groups had lower glycated hemoglobin and kidney weights and a reduced area under the curve during a glucose tolerance test, indicating improved glucose control. Epididymal fat pad weight as percent of body weight was reduced in the HV-HPMC group compared to the obese control group. The HV-HPMC group also had lower concentrations of liver lipid and cholesterol and reduced liver weight. However, HV-HPMC feeding did not affect hepatic gene expression of SREBP-1c or FAS. Muscle concentration of acylcarnitines, a lipid intermediate in fatty acid β-oxidation, was not different between the HPMC groups and obese control, suggesting no change in muscle fatty acid oxidation by HPMC. Conclusions Consumption of the viscous non-fermentable fiber HPMC decreased diabetic wasting, improved glucose control and reduced insulin resistance and fatty liver in a model of obesity with diabetes.
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Affiliation(s)
- David A Brockman
- Department of Food Science and Nutrition, University of Minnesota-Twin Cities, 1334 Eckles Avenue, St, Paul, MN 55108-1038, USA.
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35
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Crispim CA, Padilha HG, Zimberg IZ, Waterhouse J, Dattilo M, Tufik S, de Mello MT. Adipokine Levels Are Altered by Shiftwork: A Preliminary Study. Chronobiol Int 2012; 29:587-94. [DOI: 10.3109/07420528.2012.675847] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Lipidomic analysis of the liver identifies changes of major and minor lipid species in adiponectin deficient mice. Exp Mol Pathol 2012; 94:412-7. [PMID: 22465357 DOI: 10.1016/j.yexmp.2012.03.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2012] [Accepted: 03/01/2012] [Indexed: 12/18/2022]
Abstract
Adiponectin protects from hepatic fat storage but adiponectin deficient mice (APN-/-) fed a standard chow do not develop liver steatosis. This indicates that other pathways might be activated to compensate for adiponectin deficiency. An unbiased and comprehensive screen was performed to identify hepatic alterations of lipid classes in these mice. APN-/- mice had decreased hepatic cholesteryl esters while active SREBP2 and systemic total cholesterol were not altered. Upregulation of cytochromes for bile acid synthesis suggests enhanced biliary cholesterol excretion. Analysis of 37 individual fatty acid species showed reduced stearate whereas total fatty acids were not altered. Total amount of triglycerides and phospholipids were equally abundant. A selective increase of monounsaturated phosphatidylcholine and phosphatidylethanolamine which positively correlate with hepatic and systemic triglycerides with the latter being elevated in APN-/- mice, was identified. Stearoyl-CoA desaturase 1 (SCD1) is involved in the synthesis of monounsaturated fatty acids and despite higher mRNA expression enzyme activity was not enhanced. Glucosylceramide postulated to contribute to liver damage was decreased. This study demonstrates that adiponectin deficiency is associated with hepatic changes in lipid classes in mice fed a standard chow which may protect from liver steatosis.
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Ahmed MH, Barakat S, Almobarak AO. Nonalcoholic fatty liver disease and cardiovascular disease: has the time come for cardiologists to be hepatologists? J Obes 2012; 2012:483135. [PMID: 23320150 PMCID: PMC3540795 DOI: 10.1155/2012/483135] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2012] [Accepted: 11/23/2012] [Indexed: 12/21/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is prevalent in people with the metabolic syndrome and type 2 diabetes and is present in up to one-third of the general population. Evidence is now accumulating that NAFLD is associated with obesity and diabetes and may serve as a predictor of cardiovascular disease (CVD). The possible mechanisms linking NAFLD and CVD include inflammation and oxidative stress, hyperlipidaemia, insulin resistance, and direct impact of NAFLD on coronary arteries and left ventricular dysfunction. In addition, several studies suggest that NAFLD is associated with high risk of CVD and atherosclerosis such as carotid artery wall thickness and lower endothelial flow-mediated vasodilation independently of classical risk factors and components of the metabolic syndrome. It is not yet clear how treatment of NAFLD will modulate the risk of CVD. Furthermore, studies are urgently needed to establish (i) the pathophysiology of CVD with NAFLD and (ii) the benefit of early diagnosis and treatment of CVD in patients with NAFLD. In the absence of biochemical markers, it is crucial that screening and surveillance strategies are adopted in clinical practice in the growing number of patients with NAFLD and at risk of developing CVD. Importantly, the current evidence suggest that statins are safe and effective treatment for CVD in individuals with NAFLD.
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Affiliation(s)
- Mohamed H Ahmed
- Department of Medicine, Wexham Park Hospital, Berkshire, Slough, UK.
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Tan TCH, Crawford DHG, Jaskowski LA, Murphy TM, Heritage ML, Subramaniam VN, Clouston AD, Anderson GJ, Fletcher LM. Altered lipid metabolism in Hfe-knockout mice promotes severe NAFLD and early fibrosis. Am J Physiol Gastrointest Liver Physiol 2011; 301:G865-76. [PMID: 21817060 DOI: 10.1152/ajpgi.00150.2011] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The HFE protein plays a crucial role in the control of cellular iron homeostasis. Steatosis is commonly observed in HFE-related iron-overload disorders, and current evidence suggests a causal link between iron and steatosis. Here, we investigated the potential contribution of HFE mutations to hepatic lipid metabolism and its role in the pathogenesis of nonalcoholic fatty liver disease. Wild-type (WT) and Hfe knockout mice (Hfe(-/-)) were fed either standard chow, a monounsaturated low fat, or a high-fat, high-carbohydrate diet (HFD) and assessed for liver injury, body iron status, and markers of lipid metabolism. Despite hepatic iron concentrations and body weights similar to WT controls, Hfe(-/-) mice fed the HFD developed severe hypoxia-related steatohepatitis, Tnf-α activation, and mitochondrial respiratory complex and antioxidant dysfunction with early fibrogenesis. These features were associated with an upregulation in the expression of genes involved in intracellular lipid synthesis and trafficking, while transcripts for mitochondrial fatty acid β-oxidation and adiponectin signaling-related genes were significantly attenuated. In contrast, HFD-fed WT mice developed bland steatosis only, with no inflammation or fibrosis and no upregulation of lipogenesis-related genes. A HFD led to reduced hepatic iron in Hfe(-/-) mice compared with chow-fed mice, despite higher serum iron, decreased hepcidin expression, and increased duodenal ferroportin mRNA. In conclusion, our results demonstrate that Hfe(-/-) mice show defective hepatic-intestinal iron and lipid signaling, which predispose them toward diet-induced hepatic lipotoxicity, accompanied by an accelerated progression of injury to fibrosis.
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Leptin and adiponectin in obese children with and without fatty liver disease. EGYPTIAN LIVER JOURNAL 2011. [DOI: 10.1097/01.elx.0000403698.57283.fb] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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Oh HJ, Kim TH, Sohn YW, Kim YS, Oh YR, Cho EY, Shim SY, Shin SR, Han AL, Yoon SJ, Kim HC. Association of serum alanine aminotransferase and γ-glutamyltransferase levels within the reference range with metabolic syndrome and nonalcoholic fatty liver disease. THE KOREAN JOURNAL OF HEPATOLOGY 2011; 17:27-36. [PMID: 21494075 PMCID: PMC3304617 DOI: 10.3350/kjhep.2011.17.1.27] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND/AIMS Nonalcoholic fatty liver disease (NAFLD) has recently been found to be a novel component of metabolic syndrome (MS), which is one of the leading causes of chronic liver disease. The serum alanine aminotransferase (ALT) and ⟨-glutamyltransferase (GGT) levels are suggested to affect liver fat accumulation and insulin resistance. We assessed the associations of serum ALT and GGT concentrations within the reference ranges with MS and NAFLD. METHODS In total, 1,069 subjects enrolled at the health promotion center of Wonkwang University Hospital were divided into 4 groups according to serum ALT and GGT concentrations levels within the reference ranges. We performed biochemical tests, including liver function tests and lipid profiles, and diagnosed fatty liver by ultrasonography. Associations of ALT and GGT concentrationgrading within the reference range with fatty liver and/or MS were investigated. RESULTS The presence of MS, its components, and the number of metabolic abnormalities [except for high-density lipoprotein-cholesterol (HDL-C) and fasting blood glucose] increased with the ALT level, while the presence of MS, its components, and the number of metabolic abnormalities (except for HDL-C) increased with the GGT level. The odds ratios for fatty liver and MS increased with the ALT level (P⟨0.001 and P=0.049, respectively) and the GGT level (P=0.044 and P=0.039, respectively). CONCLUSIONS Serum ALT and GGT concentrations within the reference ranges correlated with the incidence of NAFLD and MS in a dose-dependent manner. There associations need to be confirmed in large, prospective studies.
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Affiliation(s)
- Hyo Jeong Oh
- Department of Internal Medicine, Sanbon Medical Center, Wonkwang University College of Medicine, Gunpo, Korea
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Wanninger J, Walter R, Bauer S, Eisinger K, Schäffler A, Dorn C, Weiss TS, Hellerbrand C, Buechler C. MMP-9 activity is increased by adiponectin in primary human hepatocytes but even negatively correlates with serum adiponectin in a rodent model of non-alcoholic steatohepatitis. Exp Mol Pathol 2011; 91:603-7. [PMID: 21791204 DOI: 10.1016/j.yexmp.2011.07.001] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2011] [Revised: 07/11/2011] [Accepted: 07/11/2011] [Indexed: 01/22/2023]
Abstract
Adiponectin protects from inflammation and fibrosis in metabolic liver disease. In the present study we analyzed whether this adipokine may directly affect the activity of matrix metalloproteinases (MMPs), central regulators of fibrinolysis, in hepatocytes. Global gene expression analysis indicated upregulation of MMP-9 and tissue inhibitor of metalloproteinases-1 (TIMP-1) expression in primary human hepatocytes (PHH) in response to stimulation with adiponectin, and these results were confirmed by real-time RT-PCR. Furthermore, gelatin zymography revealed that MMP-9 activity was significantly induced in supernatants of adiponectin stimulated PHHs. In a murine model of hepatic steatosis and in human steatotic liver samples hepatic MMP-9 activity was not significantly altered. However, in two different murine models of non-alcoholic steatohepatitis (NASH) MMP-9 activity was significantly elevated compared to chow fed control mice. Of note, MMP-9 activity did not or even negatively, respectively, correlate with adiponectin serum levels in these models. The current data indicate that in NASH hepatic inflammation and fibrosis but not hepatic steatosis induce liver MMP-9 activity, and this induction seems to be related to the anti-inflammatory activity of adiponectin rather than its effect on hepatocellular MMP-9 expression.
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Affiliation(s)
- Josef Wanninger
- Department of Internal Medicine I, Regensburg University Hospital, D-93042 Regensburg, Germany
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Heiker JT, Kosel D, Beck-Sickinger AG. Molecular mechanisms of signal transduction via adiponectin and adiponectin receptors. Biol Chem 2011; 391:1005-18. [PMID: 20536390 DOI: 10.1515/bc.2010.104] [Citation(s) in RCA: 81] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The adipocytokine adiponectin and its receptor (AdipoR) comprise a new receptor-ligand system that is involved in a variety of clinically important morbidities such as obesity, type 2 diabetes and cardiovascular diseases. Adiponectin exerts a multitude of beneficial and tissue specific effects depending on its unique, tightly regulated multimerization behavior. Post-translational modifications are essential for the multimer assembly before secretion and protein stability in the circulation. AdipoR1 and 2 have been discovered as a new class of heptahelix receptors structurally and functionally distinct from G-protein-coupled receptors. Both AdipoRs bind adiponectin and the downstream signaling of both AdipoRs is mediated mainly by phosphorylation of AMPK and activation of peroxisome proliferator-activated receptor α, which influence the lipid and glucose metabolism of skeletal muscle and liver cells as well as inflammatory processes and vascular endothelial integrity. Several intracellular binding partners of the AdipoR N-terminus such as APPL1, CK2ß; and ERp46 have been identified and shown to control receptor signaling. Adiponectin has also been reported to modulate the dimerization and internalization of AdipoRs, which provides new insights into the molecular characteristics of this unusual receptor. The understanding of the functional mechanisms of adiponectin signal transduction is critical to benefit from the full therapeutic potential of the adiponectin-AdipoR system.
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Affiliation(s)
- John T Heiker
- Institute of Biochemistry, Faculty of Life Sciences, Pharmacy and Psychology, Leipzig University, Brüderstrasse 34, D-04103 Leipzig, Germany
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Van Wagner LB, Rinella ME. The role of insulin-sensitizing agents in the treatment of nonalcoholic steatohepatitis. Therap Adv Gastroenterol 2011; 4:249-63. [PMID: 21765869 PMCID: PMC3131169 DOI: 10.1177/1756283x11403809] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome, which includes dyslipidemia, central obesity, hypertension, and insulin resistance. These diseases collectively and individually increase the risk of cardiovascular disease. Nonalcoholic steatohepatitis (NASH) is a subset of NAFLD that can progress to cirrhosis in up to 30% of patients and lead to decompensated liver disease requiring liver transplantation in many patients. Insulin resistance is the pathophysiological hallmark of NASH and addressing insulin resistance is an important aspect of NASH management. Lifestyle modifications with diet and exercise improve insulin sensitivity and are the cornerstone of therapy, but are often difficult to maintain long term. Not surprisingly, insulin-sensitizing agents have been a focus of pharmacologic investigation in NASH. Insulin sensitizers such as the thiazolidinediones, biguanides, glucagon-like peptide-1 receptor agonists, and the dipeptidyl peptidase IV inhibitors, also known as incretins, will be discussed with respect to their mechanism of action and how these drugs might target aspects of NASH pathophysiology. Finally, we will summarize the available clinical data and review both the risks and benefits of insulin sensitizers in the treatment of NASH.
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Affiliation(s)
- Lisa B Van Wagner
- Northwestern University Feinberg School of Medicine, 251 East Huron Street, Galter Pavilion, Suite 3-150, Chicago, IL 60611, USA
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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: 105] [Impact Index Per Article: 7.5] [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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Guo H, Xia M, Zou T, Ling W, Zhong R, Zhang W. Cyanidin 3-glucoside attenuates obesity-associated insulin resistance and hepatic steatosis in high-fat diet-fed and db/db mice via the transcription factor FoxO1. J Nutr Biochem 2011; 23:349-60. [PMID: 21543211 DOI: 10.1016/j.jnutbio.2010.12.013] [Citation(s) in RCA: 175] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2010] [Revised: 12/07/2010] [Accepted: 12/07/2010] [Indexed: 12/26/2022]
Abstract
Obesity is a major risk factor for the development of type 2 diabetes, and both conditions are now recognized to possess significant inflammatory components underlying their pathophysiologies. Here, we hypothesized that cyanidin 3-glucoside (C3G), a typical anthocyanin reported to possess potent anti-inflammatory properties, would ameliorate obesity-associated inflammation and metabolic disorders, such as insulin resistance and hepatic steatosis in mouse models of diabesity. Male C57BL/6J obese mice fed a high-fat diet for 12 weeks and genetically diabetic db/db mice at an age of 6 weeks received dietary C3G supplementation (0.2%) for 5 weeks. We found that dietary C3G lowered fasting glucose levels and markedly improved the insulin sensitivity in both high-fat diet fed and db/db mice as compared with unsupplemented controls. White adipose tissue messenger RNA levels and serum concentrations of inflammatory cytokines (tumor necrosis factor-α, interleukin-6, and monocyte chemoattractant protein-1) were reduced by C3G, as did macrophage infiltration in adipose tissue. Concomitantly, hepatic triglyceride content and steatosis were alleviated by C3G. Moreover, C3G treatment decreased c-Jun N-terminal kinase activation and promoted phosphorylation and nuclear exclusion of forkhead box O1 after refeeding. These findings clearly indicate that C3G has significant potency in antidiabetic effects by modulating the c-Jun N-terminal kinase/forkhead box O1 signaling pathway and the related inflammatory adipocytokines.
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Affiliation(s)
- Honghui Guo
- Guangdong Provincial Key Laboratory of Food, Department of Nutrition, School of Public Health, Sun Yat-Sen University (Northern Campus), Guangzhou 510080, China
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Wanninger J, Neumeier M, Bauer S, Weiss TS, Eisinger K, Walter R, Dorn C, Hellerbrand C, Schäffler A, Buechler C. Adiponectin induces the transforming growth factor decoy receptor BAMBI in human hepatocytes. FEBS Lett 2011; 585:1338-44. [PMID: 21496456 DOI: 10.1016/j.febslet.2011.04.003] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2010] [Revised: 04/01/2011] [Accepted: 04/01/2011] [Indexed: 02/07/2023]
Abstract
Transforming growth factor (TGF) β is the central cytokine in fibrotic liver diseases. We analyzed whether hepatoprotective adiponectin directly interferes with TGFβ1 signaling in primary human hepatocytes (PHH). Adiponectin induces the TGFβ decoy receptor BMP-and activin-membrane-bound inhibitor (BAMBI) in PHH. Overexpression of BAMBI in hepatoma cells impairs TGFβ-mediated phosphorylation of SMAD2 and induction of connective tissue growth factor. BAMBI is lower in human fatty liver with a higher susceptibility to liver fibrosis and negatively correlates with BMI of the donors. Hepatic BAMBI is reduced in rodent models of liver inflammation and fibrosis. In summary, the current data show that hepatoprotective effects of adiponectin include induction of BAMBI which is reduced in human fatty liver and rodent models of metabolic liver injury.
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Affiliation(s)
- Josef Wanninger
- Department of Internal Medicine I, University Hospital of Regensburg, Regensburg, Germany
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Guiducci L, Lionetti V, Burchielli S, Simi C, Masi S, Liistro T, Pardini S, Porciello C, Di Cecco P, Vettor R, Calcagno A, Ciociaro D, Recchia FA, Salvadori PA, Iozzo P. A dose-response elevation in hepatic glucose uptake is paralleled by liver triglyceride synthesis and release. Endocr Res 2011; 36:9-18. [PMID: 21226563 DOI: 10.3109/07435800.2010.534751] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
BACKGROUND AND AIMS Enhanced release of triglycerides (TG) by the liver is implicated in the pathogenesis of the metabolic syndrome. The aim of the study was to evaluate whether a primary elevation in hepatic glucose utilization (HGU), as induced by an acute rise in circulating glucose values during physiological hyperinsulinemia, promotes TG synthesis in spite of the reduction in free fatty acids (FFA) levels. METHODS Glucose dose-response studies were conducted in anesthetized pigs using positron emission tomography (PET) to quantify HGU during fasting euglycemic conditions (EF), and under two-step hyperglycemic hyperinsulinemia (1st-HH +3.0, 2nd-HH +6.0 mmol/L over EF glucose values). Liver biopsies were obtained in three animals to evaluate the relationship between glucose exposure and hepatic fat content. RESULTS Plasma glucose levels were progressively increased in the two-step studies, and otherwise stable within every hour of PET scanning. HGU increased almost fivefold with raising glucose levels, from 0.033 ± 0.009 in EF to 0.149 ± 0.043 in 1st-HH, p = 0.02, and to 0.138 ± 0.050 μmol/min/g in 2nd-HH, p = 0.03. Circulating TG concentrations increased by 50 and 100% in the two hyperglycemic conditions (p = 0.03 2nd-HH vs. EF), in spite of a 70% suppression in plasma FFA levels. The hepatic TG content paralleled the glucose loads. Plasma γ-glutamyl transferase (γ-GT) was increased by 17% (p < 0.05). CONCLUSIONS A short-term elevation in circulating glucose levels within the physiological postprandial range was sufficient to increase HGU, resulting in a significant synthesis and release of TG by the liver, which was accompanied by an acute rise in γ-GT and liver fat content.
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Affiliation(s)
- Letizia Guiducci
- Institute of Clinical Physiology, CNR National Research Council, Pisa, Italy
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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: 39] [Impact Index Per Article: 2.6] [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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Lucero D, Zago V, López GI, Graffigna M, Fainboim H, Miksztowicz V, Meroño T, Belli S, Levalle O, Wikinski R, Brites F, Berg G, Schreier L. Pro-inflammatory and atherogenic circulating factors in non-alcoholic fatty liver disease associated to metabolic syndrome. Clin Chim Acta 2010; 412:143-7. [PMID: 20887718 DOI: 10.1016/j.cca.2010.09.025] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2010] [Revised: 09/04/2010] [Accepted: 09/20/2010] [Indexed: 12/13/2022]
Abstract
BACKGROUND It is not elucidated if liver fat deposits associated to metabolic syndrome (MS) aggravate the atherogenic state. We evaluated, in MS patients, if the presence of non-alcoholic hepatic steatosis (HS) determines differences in inflammatory markers and VLDL characteristics. METHODS Seventy-five patients with MS were divided into 2 groups depending on the presence or absence of HS, assessed by ultrasound. Lipid profile, free fatty acids (FFA), VLDL composition, adiponectin, tumor necrosis factor-alpha (TNF-α), high sensitivity C-reactive protein (hs-CRP), and soluble adhesion molecules (sVCAM-1 and sICAM-1) were measured. RESULTS HS patients presented increased triglycerides levels, HOMA-IR and FFA. Patients with HS showed a reduction in adiponectin (p = 0.04) and increase in hs-CRP (p = 0.02), independently of insulin-resistance (IR). FFA correlated positively with TNF-α (p = 0.04) and inversely with adiponectin (p = 0.01). hs-CRP correlated with all inflammatory markers, independently of IR: TNF-α (r = 0.34, p = 0.02), sVCAM-1 (r = 0.29 p = 0.03), sICAM-1 (r = 0.56, p = 0.01), adiponectin (r = -0.34, p = 0.04). HS patients presented higher VLDL mass and number of particles. Adiponectin correlated with VLDL cholesterol content (r = -0.47, p = 0.04), independently of IR. VLDL, once secreted, would suffer from changes, becoming more atherogenic. CONCLUSIONS Simple HS would play an important role increasing cardiovascular risk, independently of IR. hs-CRP may represent a useful biomarker of this condition.
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Affiliation(s)
- Diego Lucero
- Laboratory of Lipids and Lipoproteins, Department of Clinical Biochemistry, Faculty of Pharmacy and Biochemistry, INFIBIOC, University of Buenos Aires, Argentina
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Abstract
Worldwide, the prevalence of overweight and obesity and associated complications is increasing. Cardiovascular complications are the most important factor determining survival and influencing clinical management. However, obesity is also associated with an increased risk of metabolic syndrome, type 2 diabetes, cancer and other diseases. The development of complications depends on the amount of body fat and its endocrine function. The hormones (leptin, adiponectin, resistin) and cytokines (TNF alpha, IL-6, PAI-1) produced by the adipose tissue are the link between obesity and obesity-related complications. The present article discusses the structure, function and clinical significance of adipokines.
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