Abstract
Nonalcoholic fatty liver disease is associated with obesity and insulin resistance. Factors that regulate the disposal of hepatic triglycerides contribute to the development of hepatic steatosis. G0/G1 switch gene 2 (G0S2) is a target of peroxisome proliferator-activated receptors and plays an important role in regulating lipolysis in adipocytes. Therefore, we investigated whether G0S2 plays a role in hepatic lipid metabolism. Adenovirus-mediated expression of G0S2 (Ad-G0S2) potently induced fatty liver in mice. The liver mass of Ad-G0S2-infected mice was markedly increased with excess triglyceride content compared to the control mice. G0S2 did not change cellular cholesterol levels in hepatocytes. G0S2 was found to be co-localized with adipose triglyceride lipase at the surface of lipid droplets. Hepatic G0S2 overexpression resulted in an increase in plasma Low-density lipoprotein (LDL)/Very-Low-density (VLDL) lipoprotein cholesterol level. Plasma High-density lipoprotein (HDL) cholesterol and ketone body levels were slightly decreased in Ad-G0S2 injected mice. G0S2 also increased the accumulation of neutral lipids in cultured HepG2 and L02 cells. However, G0S2 overexpression in the liver significantly improved glucose tolerance in mice. Livers expressing G0S2 exhibited increased 6-(N-(7-nitrobenz-2-oxa-1-3-diazol-4-yl) amino)-6-deoxyglucose uptake compared with livers transfected with control adenovirus. Taken together, our results provide evidence supporting an important role for G0S2 as a regulator of triglyceride content in the liver and suggest that G0S2 may be a molecular target for the treatment of insulin resistance and other obesity-related metabolic disorders.
Highlights
Hepatic steatosis, called fatty liver, is caused by the abnormal retention of triglycerides and other fats within liver cells
We found that the overexpression of G0S2 induces triglyceride accumulation in the mouse liver and results in the development of hepatic steatosis
G0S2 overexpression in the liver has beneficial effects on glucose homeostasis. These findings suggest that G0S2 is a crucial regulator of hepatic triglyceride metabolism
Summary
Called fatty liver, is caused by the abnormal retention of triglycerides and other fats within liver cells. Diabetes, and excessive alcohol consumption may contribute to hepatic steatosis [1,2,3]; more than 50% of all cases with type 2 diabetes have hepatic steatosis. High hepatic triglyceride concentrations are significantly associated with increased fasting insulin levels. It is recognized that hepatic steatosis is a predictor of insulin resistance [1,2]; hepatic steatosis is independently associated with the presence and extent of coronary artery disease and other illnesses [4,5,6]. Triglycerides accumulate in lipid droplets, and their deposition is dependent on their biosynthesis and elimination rates [7]. A decreased rate of triglyceride turnover facilitates triglyceride accumulation in the liver [8,9]. A large number of molecules can regulate the generation or disposal of hepatic triglycerides
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