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

Cell Metab. 2009 Apr;9(4):327-38. doi: 10.1016/j.cmet.2009.02.006.


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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Dietary Fats / administration & dosage
  • Dietary Fats / pharmacology
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / pathology
  • Fatty Acids / metabolism*
  • Fatty Liver / complications*
  • Fatty Liver / enzymology*
  • Feeding Behavior / drug effects
  • Gene Deletion*
  • Hepatocytes / drug effects
  • Hepatocytes / enzymology*
  • Homeostasis / drug effects
  • Inflammation / complications*
  • Inflammation / enzymology
  • Ligands
  • Lipid Metabolism / drug effects
  • Mice
  • Organ Specificity / drug effects
  • Oxidation-Reduction / drug effects
  • PPAR alpha / metabolism
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Protein Binding / drug effects
  • Signal Transduction / drug effects
  • Sirtuin 1
  • Sirtuins / genetics*
  • Sirtuins / metabolism
  • Trans-Activators / metabolism
  • Transcription Factors
  • Transcriptional Activation / drug effects


  • Dietary Fats
  • Fatty Acids
  • Ligands
  • PPAR alpha
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Trans-Activators
  • Transcription Factors
  • Sirt1 protein, mouse
  • Sirtuin 1
  • Sirtuins

Associated data

  • GEO/GSE14921