Session: SAT 723-745-Lipids: Fatty Liver Disease & Lipodystrophies
Poster Board SAT-739
Daorong Feng, Xiaoping, Zhao, Alus Xiaoli, Fajun Yang, Jeffrey E. Pessin
Dysregulation of hepatic de novo lipogenesis plays a causative role in dyslipidemia, and is closely associated with insulin resistance, type 2 diabetes, cardiovascular disease and non-alcoholic fatty liver disease (NAFLD). However, the molecular mechanisms of dysregulated de novo lipogenesis remain unclear. Previously we reported that the CDK8 complex plays an important regulatory role controlling nuclear SREBP-1c stability, SREBP-1c dependent lipogenic gene expression and de novo lipogenesis. Here we show that in genetic models of constitutive elevated de novo lipogenesis (db/db and ob/ob mice), aging mice, long term high fat diet fed mice, and human NAFLD subjects all displayed reduced levels of the CDK8 protein complex along with increased nuclear SREBP-1c protein levels, and increased lipogenic gene expression. CDK8 protein but not mRNA is upregulated in nutrient-depleted states and down regulated in nutrient abundant states in the liver, in isolated primary hepatocytes and in cultured cells. These data support a model in which the down regulation of the CDK8 protein complex results in increased levels of nuclear SREBP-1c protein that contributes, in part, to the dysregulation of liver lipogenesis in insulin resistant states.
Nothing to Disclose: DF, JEP, FY, XZ, AX
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