TY - JOUR
T1 - Hepatocyte-Specific Deletion of SIRT1 Alters Fatty Acid Metabolism and Results in Hepatic Steatosis and Inflammation
AU - Purushotham, Aparna
AU - Schug, Thaddeus T.
AU - Xu, Qing
AU - Surapureddi, Sailesh
AU - Guo, Xiumei
AU - Li, Xiaoling
N1 - Funding Information:
We thank Drs. Anton Jetten, Paul Wade, and John Cidlowski for critical reading of the manuscript and Dr. Frederic Alt at Harvard Medical School for providing the SIRT1 exon 4 floxed allele. We also thank the NIEHS microarray facility for performing the microarray experiments and Jennifer Collins for analyzing the microarray data; the NIEHS Laboratory of Experimental Pathology for histological staining and serum hormone ELISA; and the NIEHS viral core facility for lentiviruses. This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences to X.L. (Z01 ES102205).
PY - 2009/4/8
Y1 - 2009/4/8
N2 - 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.
AB - 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.
KW - HUMDISEASE
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U2 - 10.1016/j.cmet.2009.02.006
DO - 10.1016/j.cmet.2009.02.006
M3 - Article
C2 - 19356714
AN - SCOPUS:63449112017
SN - 1550-4131
VL - 9
SP - 327
EP - 338
JO - Cell Metabolism
JF - Cell Metabolism
IS - 4
ER -