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      Sirtuins and nonalcoholic fatty liver disease

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          Abstract

          Mammalian sirtuins are seven members belonging to the silent information regulator 2 family, a group of Class III histone/protein deacetylases. Sirtuins (SIRT 1-7) have different subcellular localization and function and they regulate cellular protein function through various posttranslational modifications. SIRT1 and 3, the most studied sirtuins, use the product of cellular metabolism nicotinamide adenine dinucleotide as a cofactor to post-translationally deacetylate cellular proteins and consequently link the metabolic status of the cell to protein function. Sirtuins have been shown to play a key role in the development and rescue of various metabolic diseases including non-alcoholic fatty liver disease (NAFLD). NAFLD is currently the most chronic liver disease due mainly to high-calorie consumption and lower physical activity. No pharmacological approach is available to treat NAFLD, the current recommended treatment are lifestyle modification such as weight loss through calorie restriction and exercise. Recent studies have shown downregulation of sirtuins in human as well as animal models of NAFLD indicating an important role of sirtuins in the dynamic pathophysiology of NAFLD. In this review, we highlight the recent knowledge on sirtuins, their role in NAFLD and their unique potential role as novel therapeutic target for NAFLD treatment.

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          Sirtuin activators mimic caloric restriction and delay ageing in metazoans.

          Jason Wood, Blanka Rogina, Siva Lavu … (2004)
          Caloric restriction extends lifespan in numerous species. In the budding yeast Saccharomyces cerevisiae this effect requires Sir2 (ref. 1), a member of the sirtuin family of NAD+-dependent deacetylases. Sirtuin activating compounds (STACs) can promote the survival of human cells and extend the replicative lifespan of yeast. Here we show that resveratrol and other STACs activate sirtuins from Caenorhabditis elegans and Drosophila melanogaster, and extend the lifespan of these animals without reducing fecundity. Lifespan extension is dependent on functional Sir2, and is not observed when nutrients are restricted. Together these data indicate that STACs slow metazoan ageing by mechanisms that may be related to caloric restriction.
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            Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes.

            Jill Milne, Philip Lambert, Simon Schenk … (2007)
            Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.
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              Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation.

              Aparna Purushotham, Thaddeus Schug, Qing Fang Xu … (2009)
              Hepatic metabolic derangements are key components in the development of fatty liver, insulin resistance, and atherosclerosis. SIRT1, a NAD+-dependent protein deacetylase, is an important regulator of energy homeostasis in response to nutrient availability. Here we demonstrate that hepatic SIRT1 regulates lipid homeostasis by positively regulating peroxisome proliferators-activated receptor alpha (PPARalpha), a nuclear receptor that mediates the adaptive response to fasting and starvation. Hepatocyte-specific deletion of SIRT1 impairs PPARalpha signaling and decreases fatty acid beta-oxidation, whereas overexpression of SIRT1 induces the expression of PPARalpha targets. SIRT1 interacts with PPARalpha and is required to activate PPARalpha coactivator PGC-1alpha. When challenged with a high-fat diet, liver-specific SIRT1 knockout mice develop hepatic steatosis, hepatic inflammation, and endoplasmic reticulum stress. Taken together, our data indicate that SIRT1 plays a vital role in the regulation of hepatic lipid homeostasis and that pharmacological activation of SIRT1 may be important for the prevention of obesity-associated metabolic diseases.
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                Author and article information

                Journal
                Journal ID (nlm-ta): World J Gastroenterol
                Journal ID (iso-abbrev): World J. Gastroenterol
                Journal ID (publisher-id): WJG
                Title: World Journal of Gastroenterology
                Publisher: Baishideng Publishing Group Inc
                ISSN (Print): 1007-9327
                ISSN (Electronic): 2219-2840
                Publication date (Print): 14 December 2016
                Publication date (Electronic): 14 December 2016
                Volume: 22
                Issue: 46
                Pages: 10084-10092
                Affiliations
                Fatiha Nassir, Jamal A Ibdah, Research Service, Harry S Truman Memorial VA Hospital, University of Missouri, Columbia, MO 65201, United States
                Fatiha Nassir, Jamal A Ibdah, Department of Medicine, Division of Gastroenterology and Hepatology, University of Missouri, Columbia, MO 65212, United States
                Author notes

                Author contributions: Nassir F reviewed the literature and wrote the manuscript; Ibdah JA edited the manuscript and approved the final version.

                Correspondence to: Jamal A Ibdah, MD, PhD, Professor, Director, Department of Medicine, Division of Gastroenterology and Hepatology, University of Missouri, 1 Hospital Drive, DC043.00, CE405, Columbia, MO 65212, United States. ibdahj@ 123456health.missouri.edu

                Telephone: +1-573-8827349 Fax: +1-573-8844595

                Article
                Other ID: jWJG.v22.i46.pg10084
                DOI: 10.3748/wjg.v22.i46.10084
                PMC ID: 5155167
                PubMed ID: 28028356
                SO-VID: fdcb0e43-b358-48d5-9ad8-e9d9bdb3b847
                Copyright © ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
                License:

                This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.

                History
                Date received : 16 August 2016
                Date revision received : 12 October 2016
                Date accepted : 15 November 2016
                Categories
                Subject: Review

                Keywords: sirt1,sirt3,sirtuins,non-alcoholic fatty liver disease
                Data availability:
                Keywords: sirt1, sirt3, sirtuins, non-alcoholic fatty liver disease

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