Hepatic steatosis with relation to increased expression of peroxisome proliferator-activated receptor-γ in insulin resistant mice.

We have isolated insulin resistant mice (ddY-H mice) which are spontaneously induced even if fed with the standard chow pellets. Since marked accumulation of triglycerides (TG) in liver was observed, the present study investigated causes of hepatic TG accumulation in ddY-H mice fed with the standard chow pellets. In ddY-H mice, hepatic TG content increased from seven-weeks of age, and further marked accumulation of TG was observed at 20-weeks of age. Histologically, fat droplets appeared in pericentral parenchymal cells of the liver from nine-weeks of age, and the size and number of droplets were increased in hepatic lobules at 15-weeks of age, suggesting hepatic steatosis was spontaneously induced. Although secretion of TG from liver to blood in ddY-H mice was not increased, fat absorption from the digestive tract was significantly enhanced. The mRNA expressions of peroxisome proliferator-activated receptor γ (PPARγ) involved in fat accumulation and fatty acid translocase (CD36) involved in the transportation of fatty acid into the liver were markedly increased. However, gene expressions of factors involved in lipogenesis, β-oxidation of fatty acid and lipoprotein secretion were not changed. Pioglitazone (9 mg/kg), the PPARγ agonist, administered for six weeks deteriorated hepatic steatosis in ddY-H mice. Although pioglitazone did not affect gene expressions of PPARγ in the liver, CD36 and fat-specific protein 27 (fsp27), targets of PPARγ, were markedly elevated. These results suggest that, in the livers of ddY-H mice, hepatic steatosis is induced by increased incorporation of fatty acid into the liver via increased PPARγ expression.