Overexpression of SIRT1 in adipose tissue protects liver injury caused by adiponectin deficiency in mice

Abstract

Mammalian SIRT1, a homolog of Sir2p originally discovered in S. cerevisiae, belongs to the sirtuin family of proteins. SIRT1 has been proven to improve insulin sensitivity, promote energy homeostasis and healthy aging. Adiponectin is a protein hormone that suppresses metabolic derangement associated with type 2 diabetes, obesity and non-alcoholic fatty liver diseases (NAFLD). Expression level of adiponectin is regulated in accordance with that of SIRT1. However, the detailed mechanism underlying the interrelationship between SIRT1 and adiponectin still remains unclear.

The present study aimed to investigate whether overexpression of SIRT1 in adipose tissue can rescue mice from metabolic disorders caused by adiponectin deficiency. Wild type (WT), adiponectin knock-out (AKO), adipose tissue-selective human SIRT1 transgenic (WAS), and AKO mice with human SIRT1 overexpressed in adipose tissue (WASAKO) were fed with high-fat diet for a total of eight weeks. The metabolic phenotype was examined for and compared among the four groups of mice.

The results demonstrated that overexpression of human SIRT1 in adipose tissue reduces the gain of body weight and total body fat mass associated with high-fat diet feeding, and prevents glucose intolerance, insulin resistance and hepatic injury caused by adiponectin deficiency.

AKO mice had significantly increased activity of aspartate transaminase (AST) and alanine transaminase (ALT) in circulation, malondialdehyde (MDA) content and tumor necrosis factor alpha (TNF-α) expression in liver, and accumulation of hepatic lipid droplets, all of which were prevented by selective overexpression of human SIRT1 in adipose tissues. Lipid analysis revealed that overexpression of human SIRT1 improves lipid homeostasis and prevents hepatic lipid accumulation. WASAKO mice had significantly decreased plasma cholesterol level and higher ratio of high-density lipoprotein/ low-density lipoprotein (HDL/LDL) in circulation compared with AKO mice. AKO mice had significantly elevated hepatic triglycerides level and lipid droplets accumulation, which were attenuated by overexpression human SIRT1 in adipose tissue. In addition, the hepatic gene expression levels of peroxisome proliferator-activated receptor alpha (PPARα) and fibroblast growth factor-21 (FGF-21) were significantly increased in livers of WASAKO mice, when compared to those in AKO mice.

Collectively, the present study suggests that overexpression of human SIRT1 in adipose tissue reduces lipid accumulation and inflammation in livers of adiponectin-deficient mice by promoting lipid mobilization. Further study is warranted to reveal the underlying molecular mechanisms.