Genetic defenses against noncholesterol sterols

Abstract

PURPOSE OF REVIEW This review discusses recent progress in the role of ATP-binding cassette proteins ABCG5 and G8 in dietary sterol absorption, excretion and pathogenesis of cardiovascular disease. RECENT FINDINGS Identification of the genetic defect(s) underlying sitosterolemia has led to a renewed interest in the mechanisms of sterol absorption and biliary excretion. Mutations in ABCG5 (encoding sterolin-1) or ABCG8 (encoding sterolin-2) cause this disease. These proteins are thought to function by preventing dietary noncholesterol sterols from being retained by the body and for cholesterol excretion into bile. SUMMARY Despite improvements in treatments for hypercholesterolemia with cholesterol lowering agents, cardiovascular disease still remains highly prevalent. This has prompted many to consider that molecules other than cholesterol may be better biomarkers for this disease and targeting these more directly may allow us to develop more effective therapies. Ideally, if such a biomarker were also the bioactive molecule that is key to initiating/propagating the atherosclerosis pathogenic pathway, this would allow us to develop an optimal predictor and monitor of the disease process. One source of such molecules could come from our diet, with potential candidates such as noncholesterol sterols, oxysterols, oxidized sterols or some as yet unidentified dietary bioactive molecule. Nature has evolved a protective mechanism by which such molecules are kept out of the body, thereby reducing the negative effects of these compounds. The newly identified sterolin proteins involved in the absorption and excretion of dietary sterols may fit this bill. If so, we would speculate that a better biomarker may be lurking within their substrate specificities.

Figure 1. Possible mechanism for ATP-binding cassette G5/G8 (ABCG5/G8) function in the hepatocyte and enterocyte

In the hepatocyte, ABCG5/G8 ‘pumps out’ free cholesterol and noncholesterol sterols into the bile. In the enterocyte ABCG5/G8 may function as hetero or homodimers as shown to ‘pump out’ free cholesterol and noncholesterol sterols back into the intestinal lumen. The recently released cholesterol-lowering drug Ezetimibe somehow blocks the direct absorption of micellar cholesterol. ACAT, acyl-coenzyme A: cholesterol acyltransferase; Apo, apolipoprotein; CE, cholesteryl ester; TG, triglyceride.