Mechanism of action of fibrates

Fibrates are effective in hypertriglyceridaemia and hypercholesterolaemia. They affect both triglyceride-rich and cholesterol-rich particles and have at least four separate modes of action. These include limitation of substrate availability for triglyceride synthesis in the liver; promotion of the action of lipoprotein lipase; modulation of low density lipoprotein (LDL) receptor/ligand interaction and stimulation of reverse cholesterol transport. Studies of LDL metabolism suggest the existence of two separate catabolic pathways involving the LDL receptor and scavenger mechanism(s). The former route is anti-atherogenic; the latter pro-atherogenic. At low triglyceride levels, the fractional clearance of LDL by the receptor is high. The action of fibrates is to promote the secretion of LDL which is cleared by a receptor-mediated mechanism. Catabolism of this fraction increases from 40% of the plasma pool per day in untreated to 60% per day in treated subjects. By activating lipoprotein lipase, fibrates also reduce the amount of small dense LDL, the fraction which is most likely to generate peroxidation products. Hence, fibrates stimulate LDL receptor-dependent clearance mechanisms and reduce the amount of LDL available for oxidation.