Regulation of pyruvate dehydrogenase kinase expression by the farnesoid X receptor.
The pyruvate dehydrogenase complex (PDC) functions as an important junction in intermediary metabolism by influencing the utilization of fat versus carbohydrate as a source of fuel. Activation of PDC is achieved by phosphatases, whereas, inactivation is catalyzed by pyruvate dehydrogenase kinases (PDKs). The expression of PDK4 is highly regulated by the glucocorticoid and peroxisome proliferator-activated receptors. We demonstrate that the farnesoid X receptor (FXR; NR1H4), which regulates a variety of genes involved in lipoprotein metabolism, also regulates the expression of PDK4. Treatment of rat hepatoma cells as well as human primary hepatocytes with FXR agonists stimulates the expression of PDK4 to levels comparable to those obtained with glucocorticoids. In addition, treatment of mice with an FXR agonist significantly increased hepatic PDK4 expression, while concomitantly decreasing plasma triglyceride levels. Thus, activation of FXR may suppress glycolysis and enhance oxidation of fatty acids via inactivation of the PDC by increasing PDK4 expression.
Savkur
Rajesh S
RS
Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, IN 46285, USA.
Bramlett
Kelli S
KS
Michael
Laura F
LF
Burris
Thomas P
TP
D000818:Animals; D050260:Carbohydrate Metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D005227:Fatty Acids / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D005938:Glucocorticoids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008074:Lipoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D010100:Oxygen / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000096:biosynthesis* / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014280:Triglycerides / Q000097:blood / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
D004268:DNA-Binding Proteins; D005227:Fatty Acids; D005938:Glucocorticoids; D005947:Glucose; D008074:Lipoproteins; D010100:Oxygen; D047492:Peroxisome Proliferator-Activated Receptors; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014280:Triglycerides; D000099150:Receptor, Farnesoid X-Activated; C000631432:PDK4 protein, human; C000631439:Pdk4 protein, mouse; C000631440:Pdk4 protein, rat; C403287:pyruvate dehydrogenase kinase 4