Additive effects of clofibric acid and pyruvate dehydrogenase kinase isoenzyme 4 (PDK4) deficiency on hepatic steatosis in mice fed a high saturated fat diet

Byounghoon Hwang, Pengfei Wu, Robert Harris

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

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. Here we tested whether the lipid lowering effects of clofibric acid, a PPARα agonist, are affected by PDK4 deficiency. PDK4 deficiency enhanced the beneficial effects of clofibric acid on hepatic steatosis and did not prevent its hypolipidemic effects. Therefore, PDK4 inhibitor and clofibric acid could potentially be used in combination to lower blood glucose and ameliorate hepatic steatosis.

Original languageEnglish
Pages (from-to)1883-1893
Number of pages11
JournalFEBS Journal
Volume279
Issue number10
DOIs
StatePublished - May 2012

Fingerprint

Clofibric Acid
High Fat Diet
Nutrition
Isoenzymes
Fats
Peroxisome Proliferator-Activated Receptors
Liver
Fatty Acids
Medical problems
Type 2 Diabetes Mellitus
Blood Glucose
Triglycerides
pyruvate dehydrogenase kinase 4
pyruvate dehydrogenase (acetyl-transferring) kinase
Enzyme inhibition
Lipids
Oxidation
Oxidative Phosphorylation
Dyslipidemias
Serum

Keywords

  • clofibric acid
  • diet-induced obesity
  • peroxisome proliferator-activated receptor α
  • pyruvate dehydrogenase complex
  • pyruvate dehydrogenase kinase

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Additive effects of clofibric acid and pyruvate dehydrogenase kinase isoenzyme 4 (PDK4) deficiency on hepatic steatosis in mice fed a high saturated fat diet. / Hwang, Byounghoon; Wu, Pengfei; Harris, Robert.

In: FEBS Journal, Vol. 279, No. 10, 05.2012, p. 1883-1893.

Research output: Contribution to journalArticle

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