Department of Medicine, Division of Endocrinology, Diabetes Research and Training Center, Albert Einstein College of Medicine, New York, NY, USA.
J Clin Invest. 2012 Jul;122(7):2417-27. doi: 10.1172/JCI61462. Epub 2012 Jun 11.
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.
脂质代谢异常是多种人类重大疾病的基础，包括肥胖症和 2 型糖尿病。然而，脂质代谢的病理生理学在分子水平上仍知之甚少。胰岛素通过激活 SREBP-1c 转录因子，是肝脏脂质生成的主要刺激物。在这里，我们鉴定出细胞周期蛋白依赖性激酶 8（CDK8）及其调节伙伴细胞周期蛋白 C（CycC）是果蝇、哺乳动物肝细胞和小鼠肝脏中脂质生成途径的负调控因子。CDK8 和 CycC 对从头合成脂质的抑制作用是通过 CDK8 在 SREBP-1c 的保守苏氨酸残基上磷酸化核 SREBP-1c 介导的。磷酸化作用增强了 SREBP-1c 的泛素化和蛋白降解。重要的是，与脂质生物合成的生理调节一致，CDK8 和 CycC 蛋白在进食和胰岛素的作用下迅速下调，导致 SREBP-1c 磷酸化减少。此外，CycC 的过表达有效地抑制了胰岛素和喂养诱导的脂肪生成基因表达。综上所述，这些结果表明 CDK8 和 CycC 作为胰岛素信号通路中进化保守的组成部分，在调节脂质稳态中发挥作用。
