Hepatic ABCG5/G8 overexpression reduces apoB-lipoproteins and atherosclerosis when cholesterol absorption is inhibited

Abstract

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)3LDLr-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-Tg3LDLr-KO mice. Kinetic studies revealed similar 125 I-apoB intermediate density lipoprotein/LDL fractional catabolic rates, but apoB production rates were decreased 37% in ABCG5/G8-Tg3LDLr-KO mice. Proximal aortic atherosclerosis decreased by 52% (male) and 59% (female) in ABCG5/G8-Tg3LDLr-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

The ABCs of sterol transport

“…In contrast, liverspecific transgenic mice had reduced lesions only when fed Ezetimibe (a synthetic NPC1L1 inhibitor) suggesting that intestinal sterol absorption compensates for the athero-protective effects of hepatic ABCG5/ABCG8 (49). This hypothesis is supported by the recent finding that loss of NPC1L1 reverts the sitosterolemic phenotype of Abcg5…”

Plant sterols and stanols: Their role in health and disease

“…Absence of ABCG5, ABCG8 or both results in an elevation of plant sterols in the tissues and blood and a failure to excrete sterols into bile [24][25][26][27][28][29][30][31] . Over expression of ABCG5 and ABCG8 in mice transgenic for the human genes led to a super saturation of cholesterol in bile and protected animals against atherosclerosis.…”

Ezetimibe: cholesterol lowering and beyond

“…Ezetimibe may lower plasma levels of ApoB lipoproteins through its reduction of hepatic cholesterol concentrations, leading to decreased atherogenic ApoB lipoprotein production [92]. Additionally, kinetic studies have shown that ezetimibe reduction of cholesterol delivery to the liver increases the hepatic uptake and catabolism of ApoB-100-containing lipoproteins VLDL, IDL and LDL [46], which would further reduce ApoB levels.…”