Scavenger receptor BI and ABCG5/G8 differentially impact biliary sterol secretion and reverse cholesterol transport in mice.

Biliary lipid secretion plays an important role in gallstone disease and reverse cholesterol transport (RCT). Using Sr-bI/Abcg5 double knockout mice (dko), the present study investigated the differential contribution of two of the most relevant transporters: adenosine triphosphate (ATP)-binding cassette subfamily G member 5 and 8 (ABCG5/G8) and scavenger receptor class B type I (SR-BI) to sterol metabolism and RCT. Plasma cholesterol levels increased in the following order, mainly due to differences in high density lipoprotein (HDL): Abcg5 ko < wild type < Sr-bI/Abcg5 dko < Sr-bI ko. Liver cholesterol content was elevated in Sr-bI ko only (P < 0.05). In Sr-bI/Abcg5 dko plasma plant sterols were highest, while hepatic plant sterols were lower compared with Abcg5 ko (P < 0.05). Under baseline conditions, biliary cholesterol secretion rates decreased in the following order: wild type > Sr-bI ko (-16%) > Abcg5 ko (-75%) > Sr-bI/Abcg5 dko (-94%), all at least P < 0.05, while biliary bile acid secretion did not differ between groups. However, under supraphysiological conditions, upon infusion with increasing amounts of the bile salt tauroursodeoxycholic acid, Abcg5 became fully rate-limiting for biliary cholesterol secretion. Additional in vivo macrophage-to-feces RCT studies demonstrated an almost 50% decrease in overall RCT in Sr-bI/Abcg5 dko compared with Abcg5 ko mice (P < 0.01). These data demonstrate that (1) SR-BI contributes to ABCG5/G8-independent biliary cholesterol secretion under basal conditions; (2) biliary cholesterol mass secretion under maximal bile salt-stimulated conditions is fully dependent on ABCG5/G8; and (3) Sr-bI contributes to macrophage-to-feces RCT independent of Abcg5/g8.

Dikkers A ，Freak de Boer J ，Annema W ，Groen AK ，Tietge UJ ... -  《-》

Scavenger receptor class B type I mediates biliary cholesterol secretion independent of ATP-binding cassette transporter g5/g8 in mice.

Wiersma H ，Gatti A ，Nijstad N ，Oude Elferink RP ，Kuipers F ，Tietge UJ ... -  《-》

Hepatic SR-BI, not endothelial lipase, expression determines biliary cholesterol secretion in mice.

Wiersma H ，Gatti A ，Nijstad N ，Kuipers F ，Tietge UJ ... -  《-》

Hepatic ABCG5/G8 overexpression substantially increases biliary cholesterol secretion but does not impact in vivo macrophage-to-feces RCT.

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.

Dikkers A ，de Boer JF ，Groen AK ，Tietge UJ ... -  《-》

Hepatic ABCG5 and ABCG8 overexpression increases hepatobiliary sterol transport but does not alter aortic atherosclerosis in transgenic mice.

Wu JE ，Basso F ，Shamburek RD ，Amar MJ ，Vaisman B ，Szakacs G ，Joyce C ，Tansey T ，Freeman L ，Paigen BJ ，Thomas F ，Brewer HB Jr ，Santamarina-Fojo S ... -  《JOURNAL OF BIOLOGICAL CHEMISTRY》