出版社：American Society for Biochemistry and Molecular Biology
摘要：The ATP binding cassette transporters ABCG5 (G5) and ABCG8 (G8)limit the accumulation of neutral sterols by restricting steroluptake from the intestine and promoting sterol excretion intobile. Humans and mice lacking G5 and G8 (G5G8–/–)accumulate plant sterols in the blood and tissues. However,despite impaired biliary cholesterol secretion, plasma and livercholesterol levels are lower in G5G8–/– mice thanin wild-type littermates. To determine whether the observedchanges in hepatic sterol metabolism were a direct result ofdecreased biliary sterol secretion or a metabolic consequenceof the accumulation of dietary noncholesterol sterols, we treatedG5G8–/– mice with ezetimibe, a drug that reducesthe absorption of both plant- and animal-derived sterols. Ezetimibefeeding for 1 month sharply decreased sterol absorption andplasma levels of sitosterol and campesterol but increased cholesterolin both the plasma (from 60.4 to 75.2 mg/dl) and the liver (from1.1 to 1.87 mg/g) of the ezetimibe-treated G5G8–/–mice. Paradoxically, the increase in hepatic cholesterol wasassociated with an increase in mRNA levels of HMG-CoA reductaseand synthase.
Together, these results indicate that pharmacological blockadeof sterol absorption can ameliorate the deleterious metaboliceffects of plant sterols even in the absence of G5 and G8.Supplementary key words ATP binding cassette transporter G5 • ATP binding cassette transporter G8 • sitosterolemia • cholesterol • bile
