Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation.
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.
Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Aparna
A
Purushotham
Thaddeus T
TT
Schug
Qing
Q
Xu
Sailesh
S
Surapureddi
Xiumei
X
Guo
Xiaoling
X
Li
D000818:Animals; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000473:pathology; D005227:Fatty Acids / Q000378:metabolism*; D005234:Fatty Liver / Q000150:complications* / Q000201:enzymology*; D005247:Feeding Behavior / Q000187:drug effects; D017353:Gene Deletion; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology*; D006706:Homeostasis / Q000187:drug effects; D007249:Inflammation / Q000150:complications* / Q000201:enzymology; D008024:Ligands; D050356:Lipid Metabolism / Q000187:drug effects; D051379:Mice; D009928:Organ Specificity / Q000187:drug effects; D010084:Oxidation-Reduction / Q000187:drug effects; D047493:PPAR alpha / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011485:Protein Binding / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1; D037761:Sirtuins / Q000235:genetics* / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D015533:Transcriptional Activation / Q000187:drug effects
D004041:Dietary Fats; D005227:Fatty Acids; D008024:Ligands; D047493:PPAR alpha; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins