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

Richard Roudebush Veterans Affairs Medical Center, Indianapolis, IN 46202, USA.
FEBS Journal (Impact Factor: 4). 03/2012; 279(10):1883-93. DOI: 10.1111/j.1742-4658.2012.08569.x
Source: PubMed


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.

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    • "Knocking out PDK4 could lead to higher levels of PGC1α, consistent with greater activity of PEPCK and a lower capacity for de novo fatty acid synthesis [25]. PPARα also showed coordinated regulation with PGC1α in hepatic steatosis, which was demonstrated by the enhanced beneficial effects of clofibric acid, a PPARα agonist, on fatty acid accumulation in PDK4 knockout mice [46]. In contrast to skeletal muscle, FAT/CD36, key enzymes for fatty acid transport, were not involved in the reduced fat accumulation in liver [25]. "
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    • "Moreover, Pdk4 gene expression is often induced in the liver and skeletal muscle under insulin resistance and diabetes conditions [6]–[15]. From this and other gene knockout studies [17], [18], [41], [42], it seems likely that a selective inhibition of the Pdk4 activity may be useful to normalize glucose metabolism and improve insulin resistance. "
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