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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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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    ABSTRACT: Sirtuins (SIRT), first discovered in yeast as NAD+ dependent epigenetic and metabolic regulators, have comparable activities in human physiology and disease. Mounting evidence supports that the seven-member mammalian sirtuin family (SIRT1–7) guard homeostasis by sensing bioenergy needs and responding by making alterations in the cell nutrients. Sirtuins play a critical role in restoring homeostasis during stress responses. Inflammation is designed to “defend and mend” against the invading organisms. Emerging evidence supports that metabolism and bioenergy reprogramming direct the sequential course of inflammation; failure of homeostasis retrieval results in many chronic and acute inflammatory diseases. Anabolic glycolysis quickly induced (compared to oxidative phosphorylation) for ROS and ATP generation is needed for immune activation to “defend” against invading microorganisms. Lipolysis/fatty acid oxidation, essential for cellular protection/hibernation and cell survival in order to “mend,” leads to immune repression. Acute/chronic inflammations are linked to altered glycolysis and fatty acid oxidation, at least in part, by NAD+ dependent function of sirtuins. Therapeutically targeting sirtuins may provide a new class of inflammation and immune regulators. This review discusses how sirtuins integrate metabolism, bioenergetics, and immunity during inflammation and how sirtuin-directed treatment improves outcome in chronic inflammatory diseases and in the extreme stress response of sepsis.
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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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    Full-text · Article · Jul 2015 · Metabolism: clinical and experimental
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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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