Discovery of the hepatic canalicular and intestinal cholesterol transporters. New targets for treatment of hypercholesterolemia

Arteriosclerosis and choles- terol cholelithiasis are characterized by abnor- mal regulation of cholesterol trafficking and sol- ubilization, and subsequent development of the arteriosclerotic plaque in the artery walls and gallstone formation in the gallbladder, respec- tively. Cholesterol metabolism is controlled by many complex polygenetic - environmental in- teractions that contribute to the regulation of serum lipoprotein cholesterol levels and biliary cholesterol and bile acids secretion, which con- stitute the only pathway for sterol elimination from the organism. Much of our understanding of cholesterol metabolism has arisen from stud- ies of the pathways controlling cholesterol syn- thesis and the uptake and degradation of LDL and HDL lipoproteins. Recently, two new mem- bers of the ABC transporter family (ABCG5 and ABCG8 heterodimers) have been discovered in the apical pole of the enterocyte and in the canalicular membrane of hepatocytes. Experiments in genetically engineered mice have demonstrated that ABCG5/G8 represent the physiological canalicular transporter of bil- iary cholesterol and the intestinal secretory mechanism of absorbed dietary plant sterols. Interestingly, mutation of ABCG5 and or ABCG8 genes in man causes sitosterolemia, a rare ge- netic disease characterized by massive absorp- tion of plant sterols and premature arteriosclero- sis. The potential pharmacological manipulation of biliary cholesterol secretion represents an- other important therapeutic target to treat hyper- cholesterolemia, if this manipulation is simulta- neously accompanied by measures aimed to avoid gallbladder cholesterol crystallization. The best theoretical drug should decrease serum lipoprotein cholesterol levels, increase biliary cholesterol secretion and fecal elimination and favoring at the same time gallbladder emptying to prevent gallstone formation.