Hepatocyte-Specific Deletion of SIRT1 Alters Fatty Acid Metabolism and Results in Hepatic Steatosis and Inflammation

Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Cell metabolism (Impact Factor: 17.57). 05/2009; 9(4):327-38. DOI: 10.1016/j.cmet.2009.02.006
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: Sailesh Surapureddi, Sep 26, 2015
66 Reads
  • Source
    • "In contrast, treatment with Sirt1 activators, which also results in AMPK activation [7], decreases lipogenic gene expression (SREBP-1c, ACC, FAS. SCD-1), serum lipids and fat accumulation in liver in obese insulin resistant mice [7] [8] [35]. In addition, Sirt1 and AMPK activation has beneficial effects on insulin resistance by increasing pancreatic beta-cell insulin secretion and glucose utilization in muscle, and by reducing multiple inflammatory cytokines such as TNF-α, NF-κB, and MCP-1 [15] [36] [37]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Leucine stimulates Sirt1 and AMPK signaling in vitro and in vivo. Since metformin converges on the same pathway, we have tested the ability of leucine to amplify the effects of metformin on AMPK-mediated hepatic lipid metabolism in diet-induced-obese insulin-resistant mice. Mice were fed high leucine (24g/kg diet) with or without sub-therapeutic levels of metformin (0.05-0.50g/kg diet) or therapeutic levels of metformin (1.5g/kg diet; ~300mg/kg body weight). High-fat diet produced a 10-fold increase in inguinal fat pad weight and 25% increase in liver weight, histologically confirmed as steatosis. The leucine-metformin combinations reduced fat pad mass, normalized liver weight, liver and plasma lipids and inflammatory markers (interleukin 6, interleukin 1 beta, tumor necrosis factor alpha, monocyte chemotactic protein-1, C-reactive protein) comparable to the effects of therapeutic metformin. Moreover, the highest sub-therapeutic levels of metformin with leucine exerted significantly greater effects than therapeutic levels of metformin and fully reversed hepatic steatosis. These effects were mediated by upregulation of hepatic AMPK and associated changes in lipogenic gene expression (fatty acid synthase, stearoyl CoA desaturase, acetyl CoA carboxylase) in the liver. A low-dose leucine-metformin combination exerts comparable effects on adiposity to therapeutic doses of metformin and fully reverses hepatic steatosis in diet-induced-obese mice. Copyright © 2015. Published by Elsevier Inc.
    Metabolism: clinical and experimental 07/2015; DOI:10.1016/j.metabol.2015.07.006 · 3.89 Impact Factor
  • Source
    • "Downregulation of SIRT1 significantly decreased the phosphorylation of LKB1, AMPK and ACC, and glucose stimulated the accumulation of triglyceride [93] [94]. Liver-specific SIRT1 knockout mice develop hepatic steatosis, possibly through an AMPK-mediated pathway [95] [96]. Taken together, these data indicate AMPK/SIRT1 pathway plays an important role in regulation of hepatic lipid metabolism. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Accumulation of toxic lipids is the most common etiology of insulin resistance in type 2 diabetes and associated metabolic disorders such as obesity and non-alcoholic fatty liver disease. Understanding of the underlying mechanisms has revealed various opportunities to target key regulators in lipid metabolic pathways for the treatment of metabolic diseases. Here, we review the discovery and development of potential anti-diabetic drugs with primary effects on cellular targets leading to reductions of intracellular lipids in key organs. We will particularly focus on AMPK, SIRT1, PGC-1α, SREBP-1c, ChREBP, ACC, PPARs and HSPs which either stimulate in fatty acid oxidation (energy expenditure) or inhibit de novo lipogenesis.
    Current Drug Targets 02/2015; 16(999). DOI:10.2174/1389450116666150223120829 · 3.02 Impact Factor
  • Source
    • "SIRT1 controls the expression and function of SREBP-1c and decreases hepatic lipogenesis via inhibiting the bioactivity of SREBP-1c [25]. Furthermore, SIRT1 regulates lipid homeostasis by upregulating peroxisome proliferators-activated receptor alpha (PPAR-)í µí»¼, a nuclear receptor mediating adaptive response such as fasting and starvation [26]. PPAR-í µí»¼ activation can enhance the protein level of antioxidant enzymes, such as SOD [27]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: NAFLD model rats were established and divided into NAFLD model (MG group), SIRT1 RNAi (SI group), blueberry juice (BJ group), blueberry juice + bifidobacteria (BJB group), blueberry juice + SIRT1 RNAi (BJSI group), and blueberry juice + bifidobacteria + SIRT1 RNAi groups (BJBSI group). A group with normal rats was a control group (CG). BJB group ameliorated NAFLD, which was better than BJ group (P < 0.05). The lipid accumulation was lower in CG, BJ, and BJB groups than that in MG, SI, BJSI, and BJBSI groups (P < 0.05). The levels of SIRT1 and PPAR-α were higher in CG, BJ, and BJB groups than those in MG, SI, BJSI, and BJBSI groups (P < 0.05). The levels of SREBP-1c were lower in CG, BJ, and BJB groups than those in MG, SI, BJSI, and BJBSI groups (P < 0.05). The biochemical indexes SOD, GSH, and HDL-c were improved from CG to BJB group (P < 0.05). Inversely, the levels of AST and ALT, TG, TC, LDL-c, and MDA were decreased from CG to BJB group (P < 0.05). These changes enhance antioxidative capability and biochemical index of rats. Blueberry juice and bifidobacteria improve NAFLD by activating SIRTI-mediating signaling pathway.
    Oxidative medicine and cellular longevity 11/2014; 2014:469059. DOI:10.1155/2014/469059 · 3.36 Impact Factor
Show more