Abstract
Obesity is closely associated with non-alcoholic fatty liver disease (NAFLD), and elevated serum palmitate is the link between obesity and excessive hepatic lipid accumulation. Forkhead box O-1 (FoxO1) is one of the FoxO family members of transcription factors and can stimulate adipose triglyceride lipase (ATGL) and suppress its inhibitor G0/G1 switch gene 2 (G0S2) expression in the liver. However, previous researches have also shown conflicting results regarding the role of FoxO1 in hepatic lipid accumulation. We therefore examined the role of FoxO1 as a downstream suppressor to palmitate-stimulated hepatic steatosis. Palmitate significantly promoted lipid accumulation but inhibited lipid decomposition in human HepG2 hepatoma cells. Palmitate also significantly reduced FoxO1, ATGL and its activator comparative gene identification-58 (CGI-58) expression but increased peroxisome proliferator-activated receptorγ (PPARγ) and its target gene G0S2 expression. FoxO1 overexpression significantly increased palmitate-inhibited ATGL and CGI-58 expression but reduced palmitate-stimulated PPARγ and its target gene G0S2 expression. FoxO1 overexpression also inhibited lipid accumulation and promoted lipolysis in palmitate-treated hepatocytes. Overall, these results indicate that FoxO1-mediated ATGL-dependent lipolysis may be an effective molecular mechanism in protecting hepatocytes from palmitate-induced fat accumulation.
Highlights
During the past few decades, obesity has been sharply increasing in developed and developing countries, and is a worldwide epidemic [1]
The exposure of HepG2 hepatocytes to palmitate caused a concentration-dependent decrease in lipolytic activity, as demonstrated by the glycerol and free fatty acids (FFAs) amount released into the cell media (Fig 1D and 1E)
To investigate the underlying molecular mechanism of palmitate-stimulated hepatic triglyceride accumulation, the effects of palmitate on the expression of Forkhead box O-1 (FoxO1), adipose triglyceride lipase (ATGL), comparative gene identification-58 (CGI-58), peroxisome proliferator-activated receptorγ (PPARγ), and G0S2 were evaluated in HepG2 hepatocytes
Summary
During the past few decades, obesity has been sharply increasing in developed and developing countries, and is a worldwide epidemic [1]. The global trend of obesity has led to a very high prevalence of obesity-associated non-alcoholic fatty liver disease (NAFLD) [2]. Hepatic lipid accumulation is the initial stage of NAFLD. Individuals with hepatic lipid accumulation may develop to nonalcoholic steatohepatitis, fibrosis, cirrhosis and possibly hepatocellular carcinoma progressing from simple steatosis [3]. Multiple evidences have indicated that NAFLD is associated with increased risk of developing type 2 diabetes mellitus.
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