title: Liver-specific beta-catenin knockout mice exhibit defective bile acid and cholesterol homeostasis and increased susceptibility to diet-induced steatohepatitis.
abstract: Although the role of Wnt/beta-catenin signaling in liver growth and development is well established, its contribution in non-neoplastic hepatic pathologies has not been investigated. Here, we examine the role of beta-catenin in a murine model of diet-induced liver injury. Mice with hepatocyte-specific beta-catenin deletion (KO) and littermate controls were fed the steatogenic methionine and choline-deficient (MCD) diet or the corresponding control diet for 2 weeks and characterized for histological, biochemical, and molecular changes. KO mice developed significantly higher steatohepatitis and fibrosis on the MCD diet compared with wild-type mice. Both wild-type and KO livers accumulated triglyceride on the MCD diet but, unexpectedly, higher hepatic cholesterol levels were observed in KO livers on both control and MCD diets. Gene expression analysis showed that hepatic cholesterol accumulation in KO livers was not attributable to increased synthesis or uptake. KO mice had lower expression of bile acid synthetic enzymes but exhibited higher hepatic bile acid and serum bilirubin levels, suggesting defects in bile export. Therefore, loss of beta-catenin in the liver leads to defective cholesterol and bile acid metabolism in the liver and increased susceptibility to developing steatohepatitis in the face of metabolic stress.
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Jaideep
authors.initials: J
authors.lastname: Behari
authors.forename: Tzu-Hsuan
authors.initials: TH
authors.lastname: Yeh
authors.forename: Lindsay
authors.initials: L
authors.lastname: Krauland
authors.forename: Wade
authors.initials: W
authors.lastname: Otruba
authors.forename: Benjamin
authors.initials: B
authors.lastname: Cieply
authors.forename: Beth
authors.initials: B
authors.lastname: Hauth
authors.forename: Udayan
authors.initials: U
authors.lastname: Apte
authors.forename: Tong
authors.initials: T
authors.lastname: Wu
authors.forename: Rhobert
authors.initials: R
authors.lastname: Evans
authors.forename: Satdarshan P S
authors.initials: SP
authors.lastname: Monga
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D002796:Choline Deficiency / Q000150:complications / Q000378:metabolism; D004032:Diet / Q000009:adverse effects*; D005234:Fatty Liver / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006706:Homeostasis / Q000235:genetics*; D008099:Liver / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000209:etiology; D008715:Methionine / Q000172:deficiency; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity / Q000235:genetics; D013312:Stress, Physiological / Q000502:physiology; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: D001647:Bile Acids and Salts; D051176:beta Catenin; D002784:Cholesterol; D008715:Methionine