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.