Evidence that the adenosine triphosphate‐binding cassette G5/G8‐independent pathway plays a determinant role in cholesterol gallstone formation in mice

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• 作者：Helen H. Wang ; Xiaodan Li ; Shailendra B. Patel ; David Q.‐H. Wang
• 刊名：Hepatology
• 出版年：2016
• 出版时间：September 2016
• 年：2016
• 卷：64
• 期：3
• 页码：853-864
• 全文大小：988.8KB
• ISSN：1527-3350

文摘

The adenosine triphosphate-binding cassette (ABC) sterol transporter, Abcg5/g8, is Lith9 in mice, and two gallstone-associated variants in ABCG5/G8 have been identified in humans. Although ABCG5/G8 plays a critical role in determining hepatic sterol secretion, cholesterol is still secreted to bile in sitosterolemic patients with a defect in either ABCG5 or ABCG8 and in either Abcg5/g8 double- or single-knockout mice. We hypothesize that in the defect of ABCG5/G8, an ABCG5/G8-independent pathway is essential for regulating hepatic secretion of biliary sterols, which is independent of the lithogenic mechanism of the ABCG5/G8 pathway. To elucidate the effect of the ABCG5/G8-independent pathway on cholelithogenesis, we investigated the biliary and gallstone characteristics in male wild-type (WT), ABCG5(-/-)/G8(-/-), and ABCG8 (-/-) mice fed a lithogenic diet or varying amounts of cholesterol, treated with a liver X receptor (LXR) agonist, or injected intravenously with [³H]sitostanol- and [¹⁴C]cholesterol-labeled high-density lipoprotein (HDL). We found that ABCG5(-/-)/G8(-/-) and ABCG8 (-/-) mice displayed the same biliary and gallstone phenotypes. Although both groups of knockout mice showed a significant reduction in hepatic cholesterol output compared to WT mice, they still formed gallstones. The LXR agonist significantly increased biliary cholesterol secretion and gallstones in WT, but not ABCG5(-/-)/G8(-/-) or ABCG8 (-/-), mice. The 6-hour recovery of [¹⁴C]cholesterol in hepatic bile was significantly lower in both groups of knockout mice than in WT mice and [³H]sitostanol was detected in WT, but not ABCG5(-/-)/G8(-/-) or ABCG8 (-/-), mice. Conclusions: The ABCG5/G8-independent pathway plays an important role in regulating biliary cholesterol secretion, the transport of HDL-derived cholesterol from plasma to bile, and gallstone formation, which works independently of the ABCG5/G8 pathway. Further studies are needed to observe whether this pathway is also operational in humans. (Hepatology 2016;64:853-864)