Abstract
In non-alcoholic fatty liver disease (NAFLD) and insulin resistance, hepatic de novo lipogenesis 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 mammalian target of rapamycin complex 1 (mTORC1) as a critical regulator of CDK8 and its activating 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 lipogenic enzymes are accumulated in NAFLD models. 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.
Highlights
Regulation of de novo lipogenesis in the liver is a complex process that is dependent upon the levels of nutrients and hormones, transcriptional control of lipogenic gene expression, allosteric regulation of key enzymatic activities and availability of substrates in hepatocytes [1, 2]
We have shown with multiple lines of evidence that the mammalian target of rapamycin complex 1 (mTORC1) signaling down-regulates the CDK8-CycC complex at the protein level in vivo and in vitro
We have identified the CDK8-CycC complex as a novel downstream effector of the mTORC1 signaling and our results suggest an important role of the mTORC1/CDK8 pathway in the development of non-alcoholic fatty liver disease (NAFLD)
Summary
Regulation of de novo lipogenesis in the liver is a complex process that is dependent upon the levels of nutrients and hormones, transcriptional control of lipogenic gene expression, allosteric regulation of key enzymatic activities and availability of substrates in hepatocytes [1, 2]. Sterol regulatory element-binding protein-1c (SREBP-1c) and carbohydrate responsive element-binding protein (ChREBP) are two major transcription factors that critically activate the transcription of the rate-limiting enzymes for biosynthesis of fatty acids and triglycerides [1]. De novo lipogenesis takes place primarily in hepatocytes. SREBP-1c is the primary effector of insulin-induced de novo lipogenesis in hepatocytes [3], while ChREBP is mainly activated by carbohydrates [4]. Insulin and feeding acutely stimulates SREBP-1c by increasing 1) the SREBP-1c transcript [5, PLOS ONE | DOI:10.1371/journal.pone.0126240. Insulin and feeding acutely stimulates SREBP-1c by increasing 1) the SREBP-1c transcript [5, PLOS ONE | DOI:10.1371/journal.pone.0126240 June 4, 2015
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