Hyperinsulinemic male LEW.1WR1 rats show early signs of impaired liver metabolism.

Weanling LEW.1WR1 (1WR1) rats are susceptible to type 1 diabetes (T1D) and hyperinsulinemic. Similar to human patients with T1D, these animals are susceptible to developing fatty liver infiltrates. Insulin resistance-related steatosis can lead to the development of severe forms of nonalcoholic fatty liver disease (NAFLD). Previous work in 1WR1 rats suggests that in the absence of T1D, they have increased body mass that is not reconciled by measuring their abdominal fat pads; this suggests 1WR1 rats have an underlying predisposition to store fat in the liver unrelated to diabetes status. We hypothesized that 1WR1 rats show early signs of NAFLD development. We assessed proteomics changes in the livers of glucose intolerant and hyperinsulinemic young adult 1WR1 rats to identify early detectable characteristics of NAFLD development. Our results show young adult 1WR1 rats have UBD/FAT10 gene over expression in the liver. Additionally, they have decreased mitochondrial protein levels, which may lead to lipid accumulation in the liver. A quantitative proteomic analysis showed protein expression related to branch chain fatty acid metabolism, fatty acid beta-oxidation, and oxidative phosphorylation in the liver is significantly different in 1WR1 rats compared to control LEW/SsNHsd (SsNHsd) rats. In summary, our study shows that 1WR1 rats developed early characteristics of mitochondrial dysfunction and insulin resistance in the liver independent of T1D, which are commonly observed with NAFLD development.