Article

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.

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Available from: Sailesh Surapureddi
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    • "Metabolism is known to influence aging in rodents and a number of other species of organisms56789. Several lines of evidence suggest that benefits of calorie restriction are mediated through sirtuins101112. The most convincing link between aging and sirtuins was established after the effects of aging on NAD+ were studied[13]of the functional roles of sirtuins in inflammation, other attributes such as ADP ribosylation (SIRT4) and removal of succinyl, malonyl, and glutamyl groups from lysine residues (SIRT5) may be important in inflammation[18,19]. (3) Acetyl CoA levels and its support of histone-acetylation and other proteins are linked to nutritional status of cell. Fasted or survival state of cell utilizes protein deacetylation with SIRT[20]. "
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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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