Cdc2-like kinase 2 suppresses hepatic fatty acid oxidation and ketogenesis through disruption of the PGC-1α and MED1 complex.
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.
Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
Mitsuhisa
M
Tabata
Joseph T
JT
Rodgers
Jessica A
JA
Hall
Yoonjin
Y
Lee
Mark P
MP
Jedrychowski
Steven P
SP
Gygi
Pere
P
Puigserver
D000818:Animals; D002478:Cells, Cultured; D005227:Fatty Acids / Q000378:metabolism*; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D050356:Lipid Metabolism / Q000502:physiology*; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D056913:Mediator Complex Subunit 1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D005227:Fatty Acids; C538856:Med1 protein, mouse; D056913:Mediator Complex Subunit 1; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; C066780:Clk dual-specificity kinases; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases