Effect of low doses of bezafibrate and fenofibrate on liver 2-oxoglutarate dehydrogenase complex in low-protein diet fed rats

Multienzyme 2-oxoglutarate complex (2-OGDH) together with branched chain \alpha-ketoacid dehydrogenase (BCKDH) and pyruvate dehydrogenase belong to the family of mitochondrial 2-oxoacid dehydrogenases. Hypolipidemic drugs, bezafibrate and fenofibrate, up-regulate liver BCKDH. The present study has been undertaken to determine the effect of low doses of bezafibrate and fenofibrate on liver 2-OGDH. Fibrates were administrated to rats fed low-protein diet at 5, 10 or 20 mg/kg. In rats treated with increasing doses of bezafibrate 2-OGDH activity increased by 7, 35 and 42%, while in rats administered with fenofibrate by 8, 18, and 56% (p<0.05 for bezafibrate 10 and 20, and fenofibrate 20 mg/kg). Changes in 2-OGDH activity did not correspond with changes in mRNA levels of the complex enzymes. Moreover, mRNA levels of PPAR\alpha remained unaltered. It is conceivable that stimulation of 2-OGDH activity by low doses of fibrates is the result of post-transcriptional events and may have a significant effect on liver metabolism

Low doses of fenofibrate and bezafibrate stimulate renal 2-oxoglutarate dehydrogenase (2-OGDH) in protein-restricted rats

2-oxoglutarate dehydrogenase (2-OGDH) is the key regulatory enzyme of cell metabolism. It has been previously demonstrated that in rats subjected to protein restriction low, clinically relevant doses of fibrates up-regulate liver 2-OGDH and promote 2-oxoglutarate catabolism. The aim of the present study was to evaluate the effect of low doses of fenofibrate and bezafibrate on renal 2-OGDH complex in rats fed low-protein chow. Fibrates were administered for 14 days to Wistar male rats at one daily dose of 5, 10 or 20 mg/kg b.wt./day. The 2-OGDH activity was assayed spectrophotometrically. The mRNA levels for 2-OGDH catalytic subunits (E1 and E2) and PPARα were quantified by means of semi-quantitative reverse-transcription-PCR. 2-OGDH activity increased in response to administration of fenofibrate and bezafibrate (by 11, 24, 32% and 9, 12, 21%, respectively). The difference was statistically significant for the doses of 10 and 20 mg/kg b.wt of fenofibrate (p < 0.001) and the highest dose of bezafibrate (p < 0.05). The stimulation of 2-OGDH was not accompanied by changes in mRNA levels for E1 and E2. In addition, the mRNA level for PPARα did not change. It is conceivable that fibrate-induced stimulation of 2-OGDH activity can affect renal metabolism and contribute to changes in kidney functions

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