Ablation of systemic SIRT1 activity promotes nonalcoholic fatty liver disease by affecting liver-mesenteric adipose tissue fatty acid mobilization.

Abstract

Sirtuin 1 (SIRT1) has been reported to protect against nonalcoholic fatty liver disease (NAFLD) development. The mechanism of how SIRT1 deacetylase activity affects NAFLD has not been well investigated. The current investigation addressed the causal effect of systemic SIRT1 activity on NAFLD development and the underlying mechanism involved in both liver and mesenteric adipose tissue (MAT). Both SIRT1 homozygous mice ablated the catalytic activity (sirt1Y/Y) and their corresponding wild type littermates (WT) were fed a high fat diet (HFD, 60% calories from fat) for 34weeks. Sirt1Y/Y mice showed significantly higher level of hepatic triglyceride which was accompanied with higher levels of SREBP-1 and SCD1and decreased phosphorylation of LKB1 and AMPK in the liver. Compared with WT mice, mRNA expression of lipogenic genes (lxrα, srebp-1c, scd1 and fas) in the MAT increased significantly in sirt1Y/Y mice. Fatty acid oxidation biomarkers (acox1, acox3, cpt, ucp1, sirt3) in both liver and MAT were comparable between groups. Interestingly, we observed that in sirt1Y/Y mice, the mRNA level of hormone sensitive lipase (hsl), adipose triglyceride lipase (atgl) and perilipin-2 (plin-2), all involved in lipolysis, significantly increased in MAT, but not in epididymal adipose tissue. These changes positively correlated with circulating free fatty acid (FFA) concentrations and higher hepatic mRNA expression of cd36 for FFA uptake. The present study has provided novel evidence to suggest that under HFD-induced metabolic surplus, the lack of SIRT1 catalytic activity promotes release of FFA from MAT and escalate NAFLD by interfering with lipid homeostasis in both liver and MAT.

• Authors: Junrui Cheng, Chun Liu, Kangquan Hu, Andrew Greenberg, Dayong Wu, Lynne M Ausman, Michael W McBurney, Xiang-Dong Wang
• Journal: Biochimica et biophysica acta. Molecular basis of disease (Biochim Biophys Acta Mol Basis Dis) Vol. 1863 Issue 11 Pg. 2783-2790 (11 2017) ISSN: 0925-4439 [Print] Netherlands
• PMID: 28789977 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• Fatty Acids
• Sirt1 protein, mouse
• Sirtuin 1

Topics

• Adipose Tissue (metabolism, pathology)
• Animals
• Fatty Acids (metabolism)
• Gene Expression Regulation
• Lipogenesis
• Liver (metabolism, pathology)
• Mesentery (metabolism, pathology)
• Mice
• Mice, Mutant Strains
• Non-alcoholic Fatty Liver Disease (genetics, metabolism, pathology)
• Sirtuin 1 (genetics, metabolism)