Cdc2-Like Kinase 2 Suppresses Hepatic Fatty Acid Oxidation and Ketogenesis Through Disruption of the PGC-1α and MED1 Complex

  1. Pere Puigserver1,2
  1. 1Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
  2. 2Department of Cell Biology, Harvard Medical School, Boston, MA
  1. Corresponding author: Pere Puigserver, pere_puigserver{at}


Hepatic ketogenesis plays an important role in catabolism of fatty acids during fasting along with dietary lipid overload, but the mechanisms regulating this process remain poorly understood. Here, we show that Cdc2-like kinase 2 (Clk2) suppresses fatty acid oxidation and ketone body production during diet-induced obesity. In lean mice, hepatic Clk2 protein is very low during fasting and strongly increased during feeding; however, in diet-induced obese mice, Clk2 protein remains elevated through both fed and fasted states. Liver-specific Clk2 knockout mice fed a high-fat diet exhibit increased fasting levels of blood ketone bodies, reduced respiratory exchange ratio, and increased gene expression of fatty acid oxidation and ketogenic pathways. This effect of Clk2 is cell-autonomous, because manipulation of Clk2 in hepatocytes controls genes and rates of fatty acid utilization. Clk2 phosphorylation of peroxisome proliferator–activated receptor γ coactivator (PGC-1α) disrupts its interaction with Mediator subunit 1, which leads to a suppression of PGC-1α activation of peroxisome proliferator–activated receptor α target genes in fatty acid oxidation and ketogenesis. These data demonstrate the importance of Clk2 in the regulation of fatty acid metabolism in vivo and suggest that inhibition of hepatic Clk2 could provide new therapies in the treatment of fatty liver disease.


  • Received August 27, 2013.
  • Accepted January 14, 2014.

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