title: Chronic activation of FXR in transgenic mice caused perinatal toxicity and sensitized mice to cholesterol toxicity.
abstract: The nuclear receptor farnesoid X receptor (FXR) (nuclear receptor subfamily 1, group H, member 4, or NR1H4) is highly expressed in the liver and intestine. Previous reports have suggested beneficial functions of FXR in the homeostasis of bile acids, lipids, and glucose, as well as in promoting liver regeneration and inhibiting carcinogenesis. To investigate the effect of chronic FXR activation in vivo, we generated transgenic mice that conditionally and tissue specifically express the activated form of FXR in the liver and intestine. Unexpectedly, the transgenic mice showed several intriguing phenotypes, including partial neonatal lethality, growth retardation, and spontaneous liver toxicity. The transgenic mice also displayed heightened sensitivity to a high-cholesterol diet-induced hepatotoxicity but resistance to the gallstone formation. The phenotypes were transgene specific, because they were abolished upon treatment with doxycycline to silence the transgene expression. The perinatal toxicity, which can be rescued by a maternal vitamin supplement, may have resulted from vitamin deficiency due to low biliary bile acid output as a consequence of inhibition of bile acid formation. Our results also suggested that the fibroblast growth factor-inducible immediate-early response protein 14 (Fn14), a member of the proinflammatory TNF family, is a FXR-responsive gene. However, the contribution of Fn14 induction in the perinatal toxic phenotype of the transgenic mice remains to be defined. Because FXR is being explored as a therapeutic target, our results suggested that a chronic activation of this nuclear receptor may have an unintended side effect especially during the perinatal stage.
authors.affiliation: Center for Pharmacogenetics and Department of Pharmaceutical Sciences (Q.C., Y.I., P.L., M.X., J.H., Y.Z., R.K., S.L., W.X.), and Departments of Epidemiology (R.D.L.V., R.W.E.) and Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania 15261; and Department of Pharmacology and Toxicology (G.L.G.), Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey 08854.
authors.forename: Qiuqiong
authors.initials: Q
authors.lastname: Cheng
authors.forename: Yuka
authors.initials: Y
authors.lastname: Inaba
authors.forename: Peipei
authors.initials: P
authors.lastname: Lu
authors.forename: Meishu
authors.initials: M
authors.lastname: Xu
authors.forename: Jinhan
authors.initials: J
authors.lastname: He
authors.forename: Yueshui
authors.initials: Y
authors.lastname: Zhao
authors.forename: Grace L
authors.initials: GL
authors.lastname: Guo
authors.forename: Ramalinga
authors.initials: R
authors.lastname: Kuruba
authors.forename: Rona
authors.initials: R
authors.lastname: de la Vega
authors.forename: Rhobert W
authors.initials: RW
authors.lastname: Evans
authors.forename: Song
authors.initials: S
authors.lastname: Li
authors.forename: Wen
authors.initials: W
authors.lastname: Xie
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D002784:Cholesterol / Q000633:toxicity*; D059305:Diet, High-Fat; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008107:Liver Diseases / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism; D000074050:TWEAK Receptor; D014801:Vitamin A / Q000097:blood; D014810:Vitamin E / Q000097:blood; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D002784:Cholesterol; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D000074050:TWEAK Receptor; D014801:Vitamin A; D014810:Vitamin E; D000099150:Receptor, Farnesoid X-Activated; C000613299:Tnfrsf12a protein, mouse