Document Detail

Additive effects of clofibric acid and pyruvate dehydrogenase kinase isoenzyme 4 (PDK4) deficiency on hepatic steatosis in mice fed a high saturated fat diet.
MedLine Citation:
PMID:  22429297     Owner:  NLM     Status:  MEDLINE    
Although improving glucose metabolism by inhibition of pyruvate dehydrogenase kinase 4 (PDK4) may prove beneficial in the treatment of type 2 diabetes or diet-induced obesity, it may have detrimental effects by inhibiting fatty acid oxidation. Peroxisome proliferator-activated receptor α (PPARα) agonists are often used to treat dyslipidemia in patients, especially in type 2 diabetes. Combinational treatment using a PDK4 inhibitor and PPARα agonists may prove beneficial. However, PPARα agonists may be less effective in the presence of a PDK4 inhibitor because PPARα agonists induce PDK4 expression. In the present study, the effects of clofibric acid, a PPARα agonist, on blood and liver lipids were determined in wild-type and PDK4 knockout mice fed a high-fat diet. As expected, treatment of wild-type mice with clofibric acid resulted in less body weight gain, smaller epididymal fat pads, greater insulin sensitivity, and lower levels of serum and liver triacylglycerol. Surprisingly, rather than decreasing the effectiveness of clofibric acid, PDK4 deficiency enhanced the beneficial effects of clofibric acid on hepatic steatosis, reduced blood glucose levels, and did not prevent the positive effects of clofibric acid on serum triacylglycerols and free fatty acids. The metabolic effects of clofibric acid are therefore independent of the induction of PDK4 expression. The additive beneficial effects on hepatic steatosis may be due to induction of increased capacity for fatty acid oxidation and partial uncoupling of oxidative phosphorylation by clofibric acid, and a reduction in the capacity for fatty acid synthesis as a result of PDK4 deficiency.
Byounghoon Hwang; Pengfei Wu; Robert A Harris
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2012-04-04
Journal Detail:
Title:  The FEBS journal     Volume:  279     ISSN:  1742-4658     ISO Abbreviation:  FEBS J.     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-04-23     Completed Date:  2012-07-12     Revised Date:  2014-09-14    
Medline Journal Info:
Nlm Unique ID:  101229646     Medline TA:  FEBS J     Country:  England    
Other Details:
Languages:  eng     Pagination:  1883-93     Citation Subset:  IM    
Copyright Information:
Journal compilation © 2012 FEBS. No claim to original US government works.
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MeSH Terms
Clofibric Acid / pharmacology*,  therapeutic use
Diet, High-Fat
Fatty Liver / chemically induced,  metabolism,  pathology*
Hypolipidemic Agents / pharmacology*,  therapeutic use
Isoenzymes / deficiency,  genetics,  metabolism
Mice, Knockout
Protein Kinases / deficiency*,  genetics,  metabolism
Grant Support
Reg. No./Substance:
0/Hypolipidemic Agents; 0/Isoenzymes; 53PF01Q249/Clofibric Acid; EC 2.7.-/Protein Kinases; EC 2.7.1.-/pyruvate dehydrogenase kinase 4

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