A metabolic switching hypothesis for the first step in the hypolipidemic effects of fibrates.

Pyruvate dehydrogenase kinase 4 (PDK4) mRNA was identified as a transcript that was rapidly and generally induced by fibrates in various tissues of the mouse. The time course of induction was much faster than those of typical peroxisome proliferator-activated receptor alpha (PPAR alpha)-regulated peroxisomal mRNAs. Rapid and efficient induction of PDK4 mRNA in various tissues would inactivate pyruvate dehydrogenase and stimulate fatty acid oxidation at the whole body level, leading to enhanced utilization of serum fatty acids and triglycerides. This metabolic switching mechanism can explain the early phase of the fibrate-induced decrease in the serum levels of triglycerides. Furthermore, the muscle in the fibrate-induced early state with limited activity of pyruvate dehydrogenase and low levels of fatty acids will utilize proteins as an energy source and extensive degradation of proteins may lead to myopathy or rhabdomyolysis.