FIBRATES MODIFY RAT HEPATIC FATTY-ACID CHAIN ELONGATION AND DESATURATION IN-VITRO

Three fibric acid derivatives, clofibric acid (CFB), bezafibrate (BFB) , and gemfibrozil (GFB), mainly used in the treatment of hypertriglyce ridaemic or mixed hyperlipidaemic states, have been tested for their a bility to modify fatty acid chain elongation and desaturation in vitro . Both endogenous and exogenous (saturated, monounsaturated and polyun saturated) fatty acid elongations were inhibited by fibrates at concen trations well within the physiological range (IC50 values for GFB were between 0. 1 and 0.3 mM). The potency order was GFB > BFB > CFB. Inhi bition was not due to an impairment of the activation step from free f atty acids to acyl-CoAs, as palmitoyl-CoA synthetase was only slightly inhibited (IC50 value for GFB = 2.8 mM). Fibrates (GFB) appeared to b ehave as mixed non-competitive inhibitors with respect to malonyl-CoA when the rate limiting step of elongation, the condensing enzyme, is a ssayed. Further, DELTA6 and DELTA5 desaturates were inhibited by the t hree drugs (GFB > BFB > CFB), although not to the same extent as the e longation system. In contrast, DELTA9 desaturase activity was not affe cted by fibrates.