title: Osteopontin Deficiency Alters Biliary Homeostasis and Protects against Gallstone Formation.
abstract: The precipitation of excess biliary cholesterol as solid crystals is a prerequisite for cholesterol gallstone formation, which occurs due to disturbed biliary homeostasis. Biliary homeostasis is regulated by an elaborate network of genes in hepatocytes. If unmanaged, the cholesterol crystals will aggregate, fuse and form gallstones. We have previously observed that the levels of osteopontin (OPN) in bile and gallbladder were reduced in gallstone patients. However, the role and mechanism for hepatic OPN in cholesterol gallstone formation is undetermined. In this study, we found that the expression of hepatic OPN was increased in gallstone patients compared with gallstone-free counterparts. Then, we observed that OPN-deficient mice were less vulnerable to cholesterol gallstone formation than wild type mice. Further mechanistic studies revealed that this protective effect was associated with alterations of bile composition and was caused by the increased hepatic CYP7A1 expression and the reduced expression of hepatic SHP, ATP8B1, SR-B1 and SREBP-2. Finally, the correlations between the expression of hepatic OPN and the expression of these hepatic genes were validated in gallstone patients. Taken together, our findings reveal that hepatic OPN contributes to cholesterol gallstone formation by regulating biliary metabolism and might be developed as a therapeutic target for gallstone treatments.
authors.affiliation: Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Lin
authors.affiliation: Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Lu
authors.affiliation: Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China.
authors.forename: Wei-Qing
authors.initials: WQ
authors.lastname: Shao
authors.affiliation: Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China.
authors.forename: Zong-You
authors.initials: ZY
authors.lastname: Chen
authors.affiliation: Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China.
authors.forename: Wen-Wei
authors.initials: WW
authors.lastname: Zhu
authors.affiliation: Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.affiliation: Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China.
authors.forename: Hu-Liang
authors.initials: HL
authors.lastname: Jia
authors.affiliation: Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China.
authors.forename: Duan
authors.initials: D
authors.lastname: Cai
authors.affiliation: Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China.
authors.forename: Lun-Xiu
authors.initials: LX
authors.lastname: Qin
authors.affiliation: Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China.
authors.forename: Jin-Hong
authors.initials: JH
authors.lastname: Chen
mesh_terms: D000251:Adenosine Triphosphatases / Q000096:biosynthesis; D000818:Animals; D001646:Bile / Q000737:chemistry* / Q000378:metabolism; D001652:Bile Ducts / Q000502:physiology*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000096:biosynthesis; D005260:Female; D005704:Gallbladder / Q000378:metabolism*; D042882:Gallstones / Q000473:pathology*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053495:Osteopontin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis; D051122:Scavenger Receptors, Class B / Q000096:biosynthesis; D051782:Sterol Regulatory Element Binding Protein 2 / Q000096:biosynthesis
chemical_list: D018160:Receptors, Cytoplasmic and Nuclear; C495124:SCARB1 protein, human; C497390:SREBF2 protein, human; D051122:Scavenger Receptors, Class B; D051782:Sterol Regulatory Element Binding Protein 2; C099713:nuclear receptor subfamily 0, group B, member 2; D053495:Osteopontin; C553219:CYP7A1 protein, human; D002790:Cholesterol 7-alpha-Hydroxylase; D000251:Adenosine Triphosphatases; C111067:ATP8B1 protein, human