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Deletion of SIRT1 From Hepatocytes in Mice Disrupts Lipin-1 Signaling and Aggravates Alcoholic Fatty Liver

Authors :
Xiaomei Liang
Ramon Bataller
Min You
Hu-Quan Yin
Gemma Odena
Joanne M. Ajmo
Ming Hu
Stanley M. Stevens
Xiaoling Li
Source :
Gastroenterology. 146:801-811
Publication Year :
2014
Publisher :
Elsevier BV, 2014.

Abstract

Background & Aims Sirtuin (SIRT1) is a nicotinamide adenine dinucleotide−dependent protein deacetylase that regulates hepatic lipid metabolism by modifying histones and transcription factors. Ethanol exposure disrupts SIRT1 activity and contributes to alcoholic liver disease in rodents, but the exact pathogenic mechanism is not clear. We compared mice with liver-specific deletion of Sirt1 (Sirt1LKO) mice with their LOX littermates (controls). Methods We induced alcoholic liver injury in male Sirt1LKO and control mice, placing them on Lieber-DeCarli ethanol-containing diets for 10 days and then administering a single dose of ethanol (5 g/kg body weight) via gavage. Liver and serum samples were collected. We also measured messenger RNA levels of SIRT1, SFRS10, and lipin-1β and lipin-1α in liver samples from patients with alcoholic hepatitis and individuals without alcoholic hepatitis (controls). Results On the ethanol-containing diet, livers of Sirt1LKO mice accumulated larger amounts of hepatic lipid and expressed higher levels of inflammatory cytokines than control mice; serum of Sirt1LKO mice had increased levels of alanine aminotransferase and aspartate aminotransferase. Hepatic deletion of SIRT1 exacerbated ethanol-mediated defects in lipid metabolism, mainly by altering the function of lipin-1, a transcriptional regulator of lipid metabolism. In cultured mouse AML-12 hepatocytes, transgenic expression of SIRT1 prevented fat accumulation in response to ethanol exposure, largely by reversing the aberrations in lipin-1 signaling induced by ethanol. Liver samples from patients with alcoholic hepatitis had reduced levels of SIRT1 and a higher ratio of Lpin1β/α messenger RNAs than controls. Conclusions In mice, hepatic deletion of Sirt1 promotes steatosis, inflammation, and fibrosis in response to ethanol challenge. Ethanol-mediated impairment of hepatic SIRT1 signaling via lipin-1 contributes to development of alcoholic steatosis and inflammation. Reagents designed to increase SIRT1 regulation of lipin-1 can be developed to treat patients with alcoholic fatty liver disease.

Details

ISSN :
00165085
Volume :
146
Database :
OpenAIRE
Journal :
Gastroenterology
Accession number :
edsair.doi.dedup.....13f2bd8e99834e3af8e21db559bad50a
Full Text :
https://doi.org/10.1053/j.gastro.2013.11.008