It is caused by mutations in genes encoding ATP-binding cassette, subfamily G5 (ABCG5) or G8 (ABCG8), and clinical features include elevated plant sterol levels, xanthomas, and accelerated atherosclerosis.
In conclusion, ABCG5/G8 genetic variants modulate HDL-C concentrations, leading to an HDL-C-lowering effect and thereby a potential increased risk for atherosclerosis only in smokers.
To determine whether increased expression of G5 and G8 can ameliorate hypercholesterolemia in mice lacking LDL receptors (LDLRs), we examined the effects of G5G8 transgene expression on cholesterol metabolism and atherosclerosis in Ldlr-/- mice.
To determine the specific contribution of liver ABCG5/G8 to sterol transport and atherosclerosis, we generated transgenic mice that overexpress human ABCG5 and ABCG8 in the liver but not intestine (liver G5/G8-Tg) in three different genetic backgrounds: C57Bl/6, apoE-KO, and low density lipoprotein receptor (LDLr)-KO.
These data suggest that ABCG5 and ABCG8 normally cooperate to limit intestinal absorption and to promote biliary excretion of sterols, and that mutated forms of these transporters predispose to sterol accumulation and atherosclerosis.