Format

Send to

Choose Destination
Biochim Biophys Acta Mol Basis Dis. 2017 Nov;1863(11):2783-2790. doi: 10.1016/j.bbadis.2017.08.004. Epub 2017 Aug 5.

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

Author information

1
Nutrition and Cancer Biology Lab, JM USDA-HNRCA at Tufts University, USA; Friedman School of Nutrition and Policy, Tufts University, Boston, MA, USA.
2
Nutrition and Cancer Biology Lab, JM USDA-HNRCA at Tufts University, USA.
3
Obesity and Metabolism Lab, JM USDA-HNRCA at Tufts University, USA; Friedman School of Nutrition and Policy, Tufts University, Boston, MA, USA.
4
Nutritional Immunology Lab, JM USDA-HNRCA at Tufts University, USA; Friedman School of Nutrition and Policy, Tufts University, Boston, MA, USA.
5
Department of Medicine, Microbiology and Immunology Lab, University of Ottawa, Ontario, Canada.
6
Nutrition and Cancer Biology Lab, JM USDA-HNRCA at Tufts University, USA; Friedman School of Nutrition and Policy, Tufts University, Boston, MA, USA. Electronic address: xiang-dong.wang@tufts.edu.

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.

KEYWORDS:

Adipose tissue; Lipid metabolism; Liver; Non-alcoholic fatty liver disease; Sirtuin 1

PMID:
28789977
DOI:
10.1016/j.bbadis.2017.08.004
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center