[Anti-cholesterol agents, new therapeutic approaches].

Statins and fibrates constitute the two major families of lipid-lowering agents. Statins are widely used for the treatment of pure hypercholesterolaemia while fibrates are used for the treatment of hypertriglyceridemia. Both drugs are also used for the treatment of mixed dyslipidemia. Some fibrates efficiently lower serum LDL-cholesterol. Statins inhibit HMG-CoA reductase and decrease cellular cholesterol synthesis. The resulting lower intracellular cholesterol concentration induces the activation of SREBP thus inducing the over expression and transcription of the LDL receptor gene. This over expression of the LDL receptor in the liver increases the clearance of circulating LDL thus decreasing the LDL-cholesterol plasma levels. The effects of fibrates on lipid metabolism are entirely due to their capacity to activate PPAR-alpha and to induce the over expression of genes containing a PPRE in their promoter. Fibrates decrease triglyceride concentrations by increasing the beta-oxidation of fatty acids in the liver and by decreasing triglyceride-VLDL synthesis. Fibrates also decrease triglycerides by increasing the hydolysys of triglycerides in chylomicron and VLDL through their capacity to increase and to decrease the lipoprotein lipase and the apo C-III transcription, respectively. Fibrates could decrease triglycerides partly by inducing apo A-V over-expression. These molecules increase HDL-cholesterol by increasing apo A-I and apo A-II transcription. Therefore the mechanisms of action of statins and fibrates depend on their capacity to modulate the expression of genes controlling lipoprotein metabolism.