We previously reported that liver-specific overexpression of ABCG5/G8 in mice is not atheroprotective, suggesting that increased biliary
cholesterol secretion must be coupled with decreased intestinal
cholesterol absorption to increase net
sterol loss from the body and reduce
atherosclerosis. To evaluate this hypothesis, we fed
low density lipoprotein receptor-knockout (LDLr-KO) control and ABCG5/G8-transgenic (ABCG5/G8-Tg)xLDLr-KO mice, which overexpress ABCG5/G8 only in liver, a Western diet containing
ezetimibe to reduce intestinal
cholesterol absorption. On this dietary regimen, liver-specific ABCG5/G8 overexpression increased hepatobiliary
cholesterol concentration and secretion rates (1.5-fold and 1.9-fold, respectively), resulting in 1.6-fold increased fecal
cholesterol excretion, decreased hepatic
cholesterol, and increased (4.4-fold) de novo hepatic
cholesterol synthesis versus LDLr-KO mice. Plasma
lipids decreased (total
cholesterol, 32%;
cholesteryl ester, 32%; free
cholesterol, 30%), mostly as a result of reduced non-
high density lipoprotein-cholesterol and
apolipoprotein B (
apoB; 36% and 25%, respectively).
ApoB-containing
lipoproteins were smaller and
lipid-depleted in ABCG5/G8-TgxLDLr-KO mice. Kinetic studies revealed similar 125I-apoB
intermediate density lipoprotein/
LDL fractional catabolic rates, but
apoB production rates were decreased 37% in ABCG5/G8-TgxLDLr-KO mice. Proximal aortic
atherosclerosis decreased by 52% (male) and 59% (female) in ABCG5/G8-TgxLDLr-KO versus LDLr-KO mice fed the Western/
ezetimibe diet. Thus, increased biliary secretion, resulting from hepatic ABCG5/G8 overexpression, reduces atherogenic risk in LDLr-KO mice fed a Western diet containing
ezetimibe. These findings identify distinct roles for liver and intestinal ABCG5/G8 in modulating
sterol metabolism and
atherosclerosis.