New insights into the genetic regulation of intestinal cholesterol absorption.
The small intestine is a unique organ providing dietary and reabsorbed biliary cholesterol to the body. However, the molecular mechanisms whereby cholesterol is absorbed have not yet been fully understood. Recent research suggests that the newly identified Niemann-Pick C1-like 1 protein (NPC1L1) is expressed at the apical surface of enterocytes and plays a critical role in the absorption of intestinal cholesterol. Furthermore, adenosine triphosphate (ATP)-binding cassette (ABC) transporters ABCG5 and ABCG8 represent apical sterol export pumps that promote active efflux of cholesterol and plant sterols from enterocytes back into the intestinal lumen for excretion. This provides an explanation why cholesterol absorption is a selective process, with plant sterols and other noncholesterol sterols being absorbed poorly or not at all. These findings strongly support the concept that cholesterol absorption is a multistep process, which is regulated by multiple genes at the enterocyte level. The absorption efficiency of cholesterol is most likely determined by the net effect between influx and efflux of intraluminal cholesterol molecules across the brush border of the enterocyte. Combination therapy using a novel, specific, and potent cholesterol absorption (NPC1L1) inhibitor (ezetimibe) and HMG-CoA reductase inhibitors (statins) offers an efficacious new approach to the prevention and treatment of hypercholesterolemia.
Lammert
Frank
F
Department of Medicine III, University Hospital Aachen and Aachen University, Germany.
Wang
David Q-H
DQ
D002784:Cholesterol / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D006937:Hypercholesterolemia / Q000235:genetics* / Q000503:physiopathology*; D007408:Intestinal Absorption / Q000235:genetics* / Q000502:physiology; D007421:Intestine, Small; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index
D026901:Membrane Transport Proteins; D002784:Cholesterol