RESEARCH ARTICLE mTORC1 Down-Regulates Cyclin-Dependent

In non-alcoholic fatty liver disease (NAFLD) and insulin resistance, hepatic de novo lipogen-esis is often elevated, but the underlying mechanisms remain poorly understood. Recently, we show that CDK8 functions to suppress de novo lipogenesis. Here, we identify the mam-malian target of rapamycin complex 1 (mTORC1) as a critical regulator of CDK8 and its acti-vating partner CycC. Using pharmacologic and genetic approaches, we show that increased mTORC1 activation causes the reduction of the CDK8-CycC complex in vitro and in mouse liver in vivo. In addition, mTORC1 is more active in three mouse models of NAFLD, correlated with the lower abundance of the CDK8-CycC complex. Consistent with the inhibitory role of CDK8 on de novo lipogenesis, nuclear SREBP-1c proteins and lipo-genic enzymes are accumulated in NAFLDmodels. Thus, our results suggest that mTORC1 activation in NAFLD and insulin resistance results in down-regulation of the CDK8-CycC complex and elevation of lipogenic protein expression