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      Effects of resveratrol, exercises and their combination on Farnesoid X receptor, Liver X receptor and Sirtuin 1 gene expression and apoptosis in the liver of elderly rats with nonalcoholic fatty liver

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          Abstract

          Background

          Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder. This study aims to consider effects of resveratrol, exercise and their combination on Farnesoid X receptor ( Fxr), the liver X receptor ( Lxr) and Sirtuin 1 (Sirt 1) genes expression in the liver of elderly rats with NAFLD.

          Methods

          Rats with NAFLD were randomly divided into seven groups including patient, saline, resveratrol (RSV), interval exercise, continuous exercise, interval exercise + RSV and continuous exercise + RSV. Levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) in the liver tissue were measured using specific ELISA kits. A TUNEL assay kit was used for the assessment of hepatic cells apoptosis. Lipid profiles were considered by measuring the serum triglyceride, cholesterol, LDL, and HDL. Expression of Sirt1, Lxr and Fxr genes was considered using RT-PCR.

          Results

          Resveratrol administration alone or combined with exercise training significantly improved the expression of Sirt1, Lxr and Fxr genes ( p < 0.05) in the hepatic tissue of rats with NAFLD, while levels of AST, ALT, ALP enzymes, as well as apoptotic cells were significantly decreased ( p < 0.05).

          Discussion

          Although resveratrol alone improves the expression of Sirt1, Lxr and Fxr, as well as liver function, combined therapy with exercise training is more effective to improve NAFLD.

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          Most cited references28

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          Effects of resveratrol in patients with type 2 diabetes mellitus on skeletal muscle SIRT1 expression and energy expenditure.

          The primary aims of the study were to examine the effect of resveratrol on skeletal muscle SIRT1 expression and energy expenditure in subjects with Type 2 diabetes mellitus (T2DM).
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            Mechanisms of lipotoxicity in NAFLD and clinical implications.

            With the epidemic of childhood obesity, nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease in pediatrics. NAFLD is strongly associated with insulin resistance and increased level of serum free fatty acids (FFAs). FFAs have direct hepatotoxicity through the induction of an endoplasmic reticulum stress response and subsequently activation of the mitochondrial pathway of cell death. FFAs may also result in lysosomal dysfunction and alter death receptor gene expression. Lipoapoptosis is a key pathogenic process in NAFLD, and correlates with progressive inflammation, and fibrosis. Accumulation of triglyceride in the liver results from uptake and esterification of FFAs by the hepatocyte, and is less likely to be hepatotoxic per se. To date, there are no proven effective therapies that halt NAFLD progression or unfortunately improve prognosis in children. The cellular mechanisms of lipotoxicity are complex but provide potential therapeutic targets for NAFLD. In this review we discuss several potential therapeutic opportunities in detail including inhibition of apoptosis, c-Jun-N-terminal kinase, and endoplasmic reticulum stress pathways.
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              Fatty liver diseases, bile acids, and FXR

              The prevalence of nonalcoholic fatty liver disease (NAFLD) worldwide has increased at an alarming rate, which will likely result in enormous medical and economic burden. NAFLD presents as a spectrum of liver diseases ranging from simple steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and even to hepatocellular carcinoma (HCC). A comprehensive understanding of the mechanism(s) of NAFLD-to-NASH transition remains elusive with various genetic and environmental susceptibility factors possibly involved. An understanding of the mechanism may provide novel strategies in the prevention and treatment to NASH. Abnormal regulation of bile acid homeostasis emerges as an important mechanism to liver injury. The bile acid homeostasis is critically regulated by the farnesoid X receptor (FXR) that is activated by bile acids. FXR has been known to exert tissue-specific effects in regulating bile acid synthesis and transport. Current investigations demonstrate FXR also plays a principle role in regulating lipid metabolism and suppressing inflammation in the liver. Therefore, the future determination of the molecular mechanism by which FXR protects the liver from developing NAFLD may shed light to the prevention and treatment of NAFLD.
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                Author and article information

                Contributors
                Journal
                PeerJ
                PeerJ
                peerj
                peerj
                PeerJ
                PeerJ Inc. (San Francisco, USA )
                2167-8359
                10 September 2018
                2018
                : 6
                : e5522
                Affiliations
                [1 ]Department of Exercise Physiology, Sari Branch, Islamic Azad University , Sari, Iran
                [2 ]Department of Anatomical Sciences, Faculty of Medical Sciences, Tarbiat Modares University , Tehran, Iran
                Article
                5522
                10.7717/peerj.5522
                6136396
                30221089
                f4ffeb37-22fa-44c8-ae51-907ca174b355
                ©2018 Hajighasem et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ) and either DOI or URL of the article must be cited.

                History
                : 16 February 2018
                : 4 August 2018
                Funding
                Funded by: Islamic Azad University
                This study was supported by a grant received from Islamic Azad University, Sari Branch, Iran. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Biochemistry
                Molecular Biology
                Anatomy and Physiology
                Metabolic Sciences

                resveratrol,interval exercise,nafld,continuous exercise,sirt1,lxr,fxr

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