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


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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    • "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]. "
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    Metabolism: clinical and experimental 07/2015; 64(11). DOI:10.1016/j.metabol.2015.07.006 · 3.89 Impact Factor
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    • "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. "
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    Current Drug Targets 02/2015; 16(999). DOI:10.2174/1389450116666150223120829 · 3.02 Impact Factor
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    • "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]. "
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