Dikkers Arne, de Boer Jan Freark, Groen Albert K, Tietge Uwe J F
Department of Pediatrics, The University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Department of Pediatrics, The University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Laboratory Medicine, The University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Atherosclerosis. 2015 Dec;243(2):402-6. doi: 10.1016/j.atherosclerosis.2015.10.010. Epub 2015 Oct 8.
Biliary cholesterol secretion is important for reverse cholesterol transport (RCT). ABCG5/G8 contribute most cholesterol mass secretion into bile. We investigated the impact of hepatic ABCG5/G8 on cholesterol metabolism and RCT.
Biliary and fecal sterol excretion (FSE) as well as RCT were determined using wild-type controls, Abcg8 knockout mice, Abcg8 knockouts with adenovirus-mediated hepatocyte-specific Abcg8 reinstitution and hepatic Abcg5/g8 overexpression in wild-types.
In Abcg8 knockouts, biliary cholesterol secretion was decreased by 75% (p < 0.001), while mass FSE and RCT were unchanged. Hepatic reinstitution of Abcg8 increased biliary cholesterol secretion 5-fold (p < 0.001) without changing FSE or overall RCT. Overexpression of both ABCG5/G8 elevated biliary cholesterol secretion 5-fold and doubled FSE (p < 0.001) without affecting overall RCT.
ABCG5/G8 mediate mass biliary cholesterol secretion but not from a RCT-relevant pool. Intervention strategies aiming at increasing hepatic Abcg5/g8 expression for enhancing RCT are not likely to be successful.
胆汁胆固醇分泌对胆固醇逆向转运（RCT）至关重要。ABCG5/G8对胆汁中大部分胆固醇的分泌起作用。我们研究了肝脏ABCG5/G8对胆固醇代谢和RCT的影响。
使用野生型对照、A bc g8基因敲除小鼠、通过腺病毒介导肝细胞特异性A bc g8基因重新导入的A bc g8基因敲除小鼠以及野生型中肝脏A bc g5/g8过表达小鼠，测定胆汁和粪便固醇排泄（FSE）以及RCT。
在A bc g8基因敲除小鼠中，胆汁胆固醇分泌减少了75%（p < 0.001），而粪便固醇排泄量和RCT未改变。肝脏重新导入A bc g8可使胆汁胆固醇分泌增加5倍（p < 0.001），而不改变FSE或整体RCT。ABCG5/G8两者过表达使胆汁胆固醇分泌增加5倍，FSE增加一倍（p < 0.001），但不影响整体RCT。
ABCG5/G8介导胆汁中大量胆固醇分泌，但并非来自与RCT相关的池。旨在增加肝脏A bc g5/g8表达以增强RCT的干预策略不太可能成功。
