[PDF][PDF] Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation

A Purushotham, TT Schug, Q Xu, S Surapureddi, X Guo… - Cell metabolism, 2009 - cell.com
A Purushotham, TT Schug, Q Xu, S Surapureddi, X Guo, X Li
Cell metabolism, 2009cell.com
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 α (PPARα), a nuclear receptor that mediates the
adaptive response to fasting and starvation. Hepatocyte-specific deletion of SIRT1 impairs …
Summary
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 α (PPARα), a nuclear receptor that mediates the adaptive response to fasting and starvation. Hepatocyte-specific deletion of SIRT1 impairs PPARα signaling and decreases fatty acid β-oxidation, whereas overexpression of SIRT1 induces the expression of PPARα targets. SIRT1 interacts with PPARα and is required to activate PPARα coactivator PGC-1α. 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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