title: Mice with hepatocyte-specific FXR deficiency are resistant to spontaneous but susceptible to cholic acid-induced hepatocarcinogenesis.
abstract: Farnesoid X receptor (FXR) belongs to the nuclear receptor superfamily with its endogenous ligands bile acids. Mice with whole body FXR deficiency develop liver tumors spontaneously, but the underlying mechanism is unclear. Moreover, it is unknown whether FXR deficiency in liver alone serves as a tumor initiator or promoter during liver carcinogenesis. This study aims to evaluate the effects of hepatocyte-specific FXR deficiency (FXR(hep-/-)) in liver tumor formation. The results showed that FXR(hep-/-) mice did not show spontaneous liver tumorigenesis with aging (up to 24 mo of age). Therefore FXR(hep-/-) mice were fed a bile acid (cholic acid)-containing diet alone or along with a liver tumor initiator, diethylnitrosamine (DEN). Thirty weeks later, no tumors were found in wild-type or FXR(hep-/-) mice without any treatment or with DEN only. However, with cholic acid, while only some wild-type mice developed tumors, all FXR(hep-/-) mice presented with severe liver injury and tumors. Interestingly, FXR(hep-/-) mouse livers increased basal expression of tumor suppressor p53 protein, apoptosis, and decreased basal cyclin D1 expression, which may prevent tumor development in FXR(hep-/-) mice. However, cholic acid feeding reversed these effects in FXR(hep-/-) mice, which is associated with an increased cyclin D1 and decreased cell cycle inhibitors. More in-depth analysis indicates that the increased in cell growth might result from disturbance of the MAPK and JAK/Stat3 signaling pathways. In conclusion, this study shows that hepatic FXR deficiency may only serve as a tumor initiator, and increased bile acids is required for tumor formation likely by promoting cell proliferation.
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmacy, Rutgers University, Piscataway, New Jersey;
authors.forename: Bo
authors.identifier: http://orcid.org/0000-0002-8200-7817
authors.initials: B
authors.lastname: Kong
authors.affiliation: Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China;
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of General Surgery, the Fourth Hospital of Harbin Medical University, Harbin; Division of Biobank Research, Department of General Surgery, the Fourth Hospital of Harbin Medical University, Harbin;
authors.forename: Guodong
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas;
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Williams
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmacy, Rutgers University, Piscataway, New Jersey;
authors.forename: Kyle
authors.initials: K
authors.lastname: Buckley
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas; and.
authors.forename: Ossama
authors.initials: O
authors.lastname: Tawfik
authors.affiliation: Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan.
authors.forename: James P
authors.initials: JP
authors.lastname: Luyendyk
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmacy, Rutgers University, Piscataway, New Jersey; guo@eohsi.rutgers.edu.
authors.forename: Grace L
authors.initials: GL
authors.lastname: Guo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D063646:Carcinogenesis / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D019826:Cholic Acid / Q000378:metabolism*; D019938:Cyclin D1 / Q000378:metabolism*; D004052:Diethylnitrosamine / Q000494:pharmacology; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D053612:Janus Kinases / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D023421:Models, Animal; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D019826:Cholic Acid; D019938:Cyclin D1; D004052:Diethylnitrosamine; D053612:Janus Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D018160:Receptors, Cytoplasmic and Nuclear; D050796:STAT3 Transcription Factor; D016159:Tumor Suppressor Protein p53; D000099150:Receptor, Farnesoid X-Activated
keywords: HCC; bile acids; tissue specific FXR