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

Abstract

Multienzyme 2-oxoglutarate complex (2-OGDH) together with branched chain -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 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. Article Info

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

“…Groups 5, 6 and 7: rats treated with bezafibrate (2-(4-{2-[(4-chlorophenyl)formamido]ethyl}phenoxy)-2-methylpropanoic acid) at the dose of 5; 10 and 20 mg/kg b.wt, respectively. The doses were chosen based on our earlier study on the effect of fibrates on liver 2-OGDH complex (10). Fibrates were administered by intragastric gavage for 14 days (once daily).…”

“…This effect is especially marked in rats fed a low-protein diet (7,10 high, experimental but also for low, more clinically relevant doses of fibrates. In addition, fibrates may also change mRNA levels for catalytic subunits of the complexes, though this effect is dependent on the dose used (9,10,11,12). Liver parenchymal and renal tubular cells share many of the same enzymes and metabolic pathways.…”

“…It has been shown that fibrates increase liver 2-OGDH and BCKDH complex activities and stimulate 2-OG and branched-chain amino acid catabolism, respectively (6,9). This effect is especially marked in rats fed a low-protein diet (7,10 high, experimental but also for low, more clinically relevant doses of fibrates. In addition, fibrates may also change mRNA levels for catalytic subunits of the complexes, though this effect is dependent on the dose used (9,10,11,12).…”