Mechanism of action of statins and fibrates

Statins and fibrates constitute the two major families of hypolipidaemic drugs. Statins are widely used in the treatment of patients with pure hypercholesterolaemias and mixed dyslipidaemias while fibrates are used to treat hypertriglyceridaemias and mixed hyperlipidaemias. Some fibrates efficiently reduce low density-lipoprotein (LDL)-cholesterol. Statins inhibit HMG-CoA reductase and decrease cellular cholesterol synthesis. The resulting lower intracellular cholesterol concentrations suppress the capacity of Insing-1 and Insing-2 to inhibit the interaction of SCAP with SREBP-2 in the membrane of the endoplasmic reticulum and the formation of the SCAP: SREBP-2:SP-1 complex. When formed, this complex migrates towards the Golgi where activated SP-1 and SP-2 protease cleave SREBP-2 to give a free NH2-terminal-SREBP-2 peptide which migrates towards the nucleus. In the nucleus, this free NH2-terminal-SREBP-2 peptide binds to the SIZE contained in the promoter of the gene of the LDL(B/E)-receptor and induces the transcription of this gene, and the over-expression of the LDL(B/E)-receptor in the cytoplasmic plasma membrane of hepatocytes. The over-expression of the LDL-receptor in the liver increases the clearance of circulating LDL, decreasing the LDL-cholesterol plasma levels. Fibrates decrease plasma triglycerides by decreasing their hepatic synthesis and increasing their catabolism. They decrease the triglyceride-very low density-lipoprotein (VLDL) synthesis through their capacity to increase the beta-oxidation of fatty acids in the liver. They increase the plasma triglyceride catabolism by inducing the lipoprotein lipase gene transcription and decreasing the apoC-III gene transcription. Fibrates increase high density-lipoprotein (HDL)-cholesterol by increasing apoA-I and apoA-II gene transcription. These bio-molecular effects of fibrates are entirely due to their capacity to activate PPARalpha and to induce the over expression of genes containing a PPRE in their promoter. Therefore, the mechanism of action of the statins and fibrates depends on their capacity to modulate the expression of genes controlling the lipoprotein metabolism.