PubMed · 12763379
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Bruno Stieger. 2003. Biliary cholesterol secretion: more lessons from plants?. https://doi.org/10.1016/s0168-8278(03)00194-6
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BACKGROUND AND AIM: The liver and small intestine play an important role in maintaining cholesterol and bile acid balance within the body. The purpose of this study was to evaluate the effect of bile duct ligation (BDL) on the expression of intestinal and hepatic genes that are important for cholesterol and bile acid metabolism. METHODS: Rats were allocated to the BDL group or the sham operation group. Blood, liver and small intestine were obtained after 24, 72 and 168 h from both groups. Serum and hepatic lipids were measured by colorimetric assays and hepatic and intestinal mRNA related to lipid metabolism was studied by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Hepatic apolipoprotein (Apo) AIV, multidrug resistant protein (Mrp)2, adenosine triphosphate (ATP) binding cassette transporter (Abc)g5 and Abcg8 expression constantly decreased after BDL. Intestinal Apo AIV, Apo CIII, Mrp2, Abcg5 and Abcg8 expression remarkably decreased 24 h after BDL and recovered 72 and 168 h after BDL. Hepatic small heterodimer partner (Shp) expression did not change after BDL. Conversely, intestinal Shp expression remarkably decreased 24 h after BDL (16% of sham operation) and slightly recovered 168 h after BDL (58% of sham operation). CONCLUSION: Several intestinal mRNA expressions important for lipid (Apo AIV, Apo CIII, Abcg5 and Abcg8) and bile acid (Mrp2 and Shp) metabolism were decreased in the early phase of obstructive jaundice and the expression of these intestinal mRNA recovered in the late phase of obstructive jaundice.
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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.