Abstract
BackgroundCholesterol gallstone disease is a very common disease in both industrialized and developing countries. Many studies have found that cholesterol gallstones are more common in women than men. The molecular mechanisms underlying the relationship between female gallstone disease and hepatic sterol transporters are still undergoing definition and have not been evaluated in humans.AimsThe aim of this study is to probe for underlying hepatic molecular defects associated with development of gallstones in female.Methods/ResultsFifty-seven nonobese, normolipidemic Chinese female gallstone patients (GS) were investigated with 12 age- and body mass index-matched female gallstone-free controls (GSF). The bile from the female GS had higher cholesterol saturation than that from the female GSF. The hepatic NPC1L1 mRNA levels were lower in female GS, correlated with SREBP2 mRNA. NPC1L1 downregulation was confirmed at protein levels. Consistently, immunohistochemistry showed decreased NPC1L1 expression in female GS.ConclusionsThe decreased hepatic NPC1L1 levels in female GS might indicate a downregulated reabsorption of biliary cholesterol in the liver, which, in turn, leads to the cholesterol supersaturation of bile. Our data are consistent with the possibility that hepatic NPC1L1 may be mediated by SREBP2.
Highlights
Cholesterol gallstone disease is common in both industrialized and developing countries [1,2]
The decreased hepatic NPC1L1 levels in female gallstone patients (GS) might indicate a downregulated reabsorption of biliary cholesterol in the liver, which, in turn, leads to the cholesterol supersaturation of bile
There were no differences in hepatic ABCG5, ABCG8 and LXRa mRNA expression between female GS and female gallstone-free controls (GSF) in our study, we found that ABCG5 and ABCG8 mRNA levels correlated very well (r = 0.69, P < 0.01) (Fig. 1C), confirming their likely coexpression in human liver in vivo, as we previously have observed in liver tissue [5]
Summary
Cholesterol gallstone disease is common in both industrialized and developing countries [1,2]. A large number of human and animal studies have proposed that estrogen increases the risk of Hypersecretion of biliary cholesterol and cholesterol supersaturation of the bile are considered to be the most important prerequisites for gallstone formation. We observed that Chinese gallstone patients had an increased hepatic ABCG5/ABCG8 expression [5]. Study found no relationship exists between biliary cholesterol excretion and hepatic ABCG5 and ABCG8 gene expression in human liver transplantation patients [6]. The existence of novel mechanisms other than ABCG5/ABCG8 in regulating biliary cholesterol secretion has been suggested based on several recent observations in mice [7,8]. Cholesterol gallstone disease is a very common disease in both industrialized and developing countries. The molecular mechanisms underlying the relationship between female gallstone disease and hepatic sterol transporters are still undergoing definition and have not been evaluated in humans
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