Mammalian target of the rapamycin pathway is involved in non-alcoholic fatty liver disease

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a common liver disease associated with an increased risk of type 2 diabetes and cardiovascular disease. Many factors may contribute to NAFLD development and progression, but the exact mechanisms are still not fully understood. In this study, Sprague-Dawley rats were fed either a standard diet (control group), a high-fat diet for 8 weeks (the HFD-8 group) or a high-fat diet for 16 weeks (the HFD-16 group). The HFD animals showed high levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and insulin resistance index (Homa-IR). Mild and severe steatosis was found in both the HFD-8 and HFD-16 groups, respectively. Compared with the controls, mRNA levels of mTOR, S6K1, IL-1α, IL-6 and TNFα were significantly increased in the HFD-8 and HFD-16 groups. IRS-1 mRNA was significantly increased in the HFD-8 group, but not in the HFD-16 group. The protein levels of mTOR, pmTOR(Ser2448), S6K1, pIRS-1(Ser307), IL-1α and IL-6 were significantly increased in the HFD-8 and HFD-16 groups. The protein levels of pmTOR(Ser2448) and IL-1α were significantly higher in the HFD-16 group compared to those in the HFD-8 group. However, the protein expression level of mTOR did not differ significantly between the HFD-8 and HFD-16 groups. The pIRS-1(Tyr102) level was significantly lower in both the HFD-8 and HFD-16 groups when compared to that in the control group, and the pIRS-1(Tyr102) level was significantly lower in the HFD-16 group compared to that of the HFD-8 group. pmTOR(Ser2448) was positively correlated with the TNFα mRNA level, and pIRS-1(Ser307) was positively correlated with pmTOR(Ser2448), TNFα, S6K1 and mTOR. pIRS-1(Tyr102) was negatively correlated with pmTOR(Ser2448), TNFα, S6K1 and mTOR. These data indicate that mTOR contributes to insulin resistance and chronic liver inflammation, and may play an important role in the development and progression of NAFLD.