Key result
CDK8 and CycC negatively regulate de novo lipogenesis by phosphorylating nuclear SREBP-1c to promote its degradation, and are themselves downregulated by feeding and insulin.
CDK8 and CycC are identified as evolutionarily conserved negative regulators of lipid homeostasis and the insulin signaling pathway via SREBP-1c degradation.
Identifies CDK8/CycC as conserved lipogenesis regulators in mice; leaves open human therapeutic translation.
Altered lipid metabolism underlies several major human diseases, including obesity and type 2 diabetes. However, lipid metabolism pathophysiology remains poorly understood at the molecular level. Insulin is the primary stimulator of hepatic lipogenesis through activation of the SREBP-1c transcription factor. Here we identified cyclin-dependent kinase 8 (CDK8) and its regulatory partner cyclin C (CycC) as negative regulators of the lipogenic pathway in Drosophila, mammalian hepatocytes, and mouse liver. The inhibitory effect of CDK8 and CycC on de novo lipogenesis was mediated through CDK8 phosphorylation of nuclear SREBP-1c at a conserved threonine residue. Phosphorylation by CDK8 enhanced SREBP-1c ubiquitination and protein degradation. Importantly, consistent with the physiologic regulation of lipid biosynthesis, CDK8 and CycC proteins were rapidly downregulated by feeding and insulin, resulting in decreased SREBP-1c phosphorylation. Moreover, overexpression of CycC efficiently suppressed insulin and feeding-induced lipogenic gene expression. Taken together, these results demonstrate that CDK8 and CycC function as evolutionarily conserved components of the insulin signaling pathway in regulating lipid homeostasis.
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Zhao et al. (2012) studied Lipid metabolism. CDK8 and CycC knockdown or overexpression vs. Wild-type or non-silencing control was evaluated on Lipid accumulation and lipogenic gene expression. CDK8 and CycC negatively regulate de novo lipogenesis by phosphorylating nuclear SREBP-1c to promote its degradation, and are themselves downregulated by feeding and insulin.
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