Exacerbation of dietary steatohepatitis and fibrosis in obese, diabetic KK-A(y) mice.

In this study, we investigated a dietary model of steatohepatitis caused by methionine- and choline-deficiency (MCD) in obese, diabetic KK-A(y) mice. Male KK-A(y) mice and C57Bl/6 mice were fed an MCD diet for up to 8 weeks, and liver pathology was evaluated. Hepatic steatosis and inflammatory infiltration were more prominent in KK-A(y) mice than in C57Bl/6 mice 4 weeks after feeding with MCD diet. MCD diet-induced increases in tumor necrosis factor (TNF)-alpha mRNA levels, as well as lipid peroxidation, in the liver were also potentiated significantly in KK-A(y) mice. Extended degree of hepatic fibrosis was observed in KK-A(y) mice as compared to C57Bl/6 mice 8 weeks after feeding with MCD diet. Indeed, alpha1(I)procollagen and transforming growth factor (TGF)-beta1 mRNA levels were significantly higher in KK-A(y) mice following dietary treatment. Serum adiponectin levels were elevated nearly two-fold when C57Bl/6 mice were given MCD diet for 4 weeks; however, serum adiponectin levels in KK-A(y) mice fed both the control- and MCD diet were the same, reaching the values almost 1/2 of those in C57Bl/6 mice. In conclusion, KK-A(y) mice exhibit increased susceptibility to MCD diet-induced steatohepatitis, where hypoadiponectinemia most likely plays a key role in exacerbation of both inflammatory and profibrogenic responses.