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

Abstract

The incidence of nonalcoholic fatty liver disease (NAFLD) is escalating paralleled with obesity rates in both adults and children. Mammalian sirtuin 1 (SIRT1), a highly conserved NAD+‐dependent protein deacetylase, has been identified as a metabolic regulator of lipid homeostasis and a potential target for NAFLD prevention and treatment. However, the mechanism of how SIRT1, in particularly its 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 potential mechanism involved in both liver and mesenteric adipose tissue. At 6 weeks of age, both SIRT1 homozygous mice carrying a point mutation (H355Y, SIRT1Y/Y, n=10) that ablates the catalytic activity and their corresponding wild type littermates (WT, n=10) were fed with high fat diet (HFD, 60% calories from fat) for 34 weeks. Results showed no changes of body weight, liver weight and body composition (anlyzed by EchoMRI‐700) between WT and SIRT1Y/Y mice, but SIRT1Y/Y mice showed significantly higher level of hepatic triglyceride, and a trend of more severe hepatic steatosis by pathological analysis, which was accompanied with higher protein levels of LXRα, SREBP‐1, SCD1, involved in lipogenesis, and decreased phosphorylation of LKB1 and AMPK in the liver. In the mesenteric adipose tissue, mRNA expression of lipogenic genes (lxrα, srebp‐1c, scd1 and fas) increased significantly in SIRT1Y/Y mice, as compared with those of wild‐type mice. Fatty acid oxidation biomarkers (acox1, acox3, cpt, ucp1, sirt3) in both liver and mesenteric adipose tissue 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, involved in lipolysis, significantly increased in mesenteric adipose tissue (not in epididymal adipose tissue), as compared with those of WT. These changes were correlated with higher circulating free fatty acid (FFA) concentrations and higher hepatic mRNA expression of cd36 for FFA uptake. Taken together, the present study provided novel experimental evidence that under HFD‐induced metabolic surplus, the lack of SIRT1 catalytic activity promoted release of FFA from mesenteric fat into systemic circulation and escalated NAFLD by interfering with lipid homeostasis in both liver and mesenteric adipose tissue.Support or Funding InformationSupported by USDA/NIFA (2015‐67017) and USDA/ARS (58‐1950‐0014)