Because intestinal cholesterol absorption is a major determinant of serum low-density lipoprotein (LDL) cholesterol concentrations, understanding the genetic regulation of cholesterol absorption may lead to novel approaches to the treatment of cardiovascular diseases that affect millions of people in Westernised societies. Recent research suggests that ATP-binding cassette (ABC) transporters ABCG5 and ABCG8 represent an apical sterol export pump that may promote active efflux of cholesterol and plant sterols from enterocytes back into the intestinal lumen for excretion. The newly identified Niemann-Pick C1 like 1 (NPC1L1) protein is also expressed at the apical surface of enterocytes and plays a critical role in the ezetimibe-sensitive cholesterol absorption pathway. These findings strongly support the notion that cholesterol absorption is a multistep process that is regulated by multiple genes at the enterocyte level. The efficiency of cholesterol absorption could be determined by the net effect between influx and efflux of intraluminal cholesterol molecules across the brush border of the enterocyte. Ezetimibe is a novel, specific and potent cholesterol absorption inhibitor that effectively blocks intestinal absorption of dietary and biliary cholesterol. It decreases serum LDL cholesterol levels up to 20%. Such effects are needed in the therapy of difficult-to treat lipid disorders, including the rare homozygous familial hypercholesterolemia and sitosterolemia. The efficacy, safety, and tolerability of both ezetimibe monotherapy and coadministration therapy with a statin have been evaluated in clinical trials. Combination therapy using cholesterol absorption (NPC1L1) inhibitor (ezetimibe) and HMG-CoA reductase inhibitors (statins) offers an efficacious new strategy for the prevention and treatment of hypercholesterolemia.
- Bile acid
- Cholesterol transporter
- Plant sterol
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine