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

Abstract

Background&Aims: Sirtuin (SIRT1) is a NAD+-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 (ALD) 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 mRNA levels of SIRT1, SFRS10, and lipin-1β and lipin-1α in liver samples from patients with alcoholic hepatitis (AH) and individuals without AH (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 AH had reduced levels of SIRT1 and a higher ratio of Lpin1β:α mRNAs 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 might be developed to treat patients with alcoholic fatty liver disease.

The Detrimental Role Played by Lipocalin-2 in Alcoholic Fatty Liver in Mice

“…Consistent with these in vitro findings, LCN2 protein levels were substantially increased in the serum samples from the previously studied ethanol-fed WT mice, and further significantly augmented in the ethanol-fed liver-specific deletion of Sirt1 (Sirt1LKO) mice (Supplemental Figure S6). 18 Taken together, these results suggested that ethanolmediated perturbation of miR-217-SIRT1 axis led to LCN2 induction in hepatocytes. Given that LCN2 inhibits SIRT1, miR-217-SIRT1 axis may constitute a positive regulatory loop in the up-regulation of LCN2 by ethanol.…”

“…More surprisingly, we found that removal of LCN2 did not alter steatosis in mice when ethanol was administrated with a chronicbinge ethanol feeding protocol (referred as Gao-binge ethanol treatment model) (data not shown). 18,25 Therefore, it is likely that LCN2 selectively involves in the development and progression of chronically ethanol-induced steatosis.…”

“…18,19 However, removal of LCN2 largely abolished the elevation of SAA-1 mRNA levels in the livers of Lcn2KO mice fed either with or without ethanol (Figure 3).…”

“…18,19 Transfection, Luciferase Reporter Assay, and Adenovirus (Ad) Infection Studies in Mouse AML-12 Hepatocytes…”

The metal nanoparticle-induced inflammatory response is regulated by SIRT1 through NF-κB deacetylation in aseptic loosening

“…19,22 Furthermore, clinical evidence suggests that SIRT1 downregulation is closely correlated with inflammatory diseases, while the pharmacological activation of SIRT1 by resveratrol effectively attenuates inflammatory injuries. [23][24][25][26] Therefore, the aims of this study were to examine the effects of metal nanoparticles on SIRT1 and proinflammatory cytokine expression in macrophages and clinical specimens from patients with prosthesis loosening and to investigate the potential role of SIRT1 in inflammatory responses in the pathological process of aseptic loosening.…”