title: Suppression of autophagic flux by bile acids in hepatocytes.
abstract: Retention of bile acids (BAs) in the liver during cholestasis plays an important role in the development of cholestatic liver injury. Several studies have reported that high concentrations of certain BAs induce cell death and inflammatory response in the liver, and BAs may promote liver tumorigenesis. Macroautophagy (hereafter referred to as autophagy) is a lysosomal degradation process that regulates organelle and protein homeostasis and serves as a cell survival mechanism under a variety of stress conditions. However, it is not known if BAs modulate autophagy in hepatocytes. In the present study, we determined autophagic flux in livers of farnesoid X receptor (FXR) knockout (KO) mice that have increased concentrations of hepatic BAs and in primary cultured mouse hepatocytes treated with BAs. The results showed that autophagic flux was impaired in livers of FXR KO mice and in BA-treated primary mouse hepatocytes. Mechanistically, BAs did not affect the activities of cathepsin or the proteasome, but impaired autophagosomal-lysosomal fusion likely due to reduction of Rab7 protein expression and targeting to autophagosomes. In conclusion, BAs suppress autophagic flux in hepatocytes by impairing autophagosomal-lysosomal fusion, which may be implicated in bile acid-induced liver tumor promotion observed in FXR KO mice.
authors.affiliation: * Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS 66160.
authors.forename: Sharon
authors.initials: S
authors.lastname: Manley
authors.forename: Hong-Min
authors.initials: HM
authors.lastname: Ni
authors.forename: Bo
authors.initials: B
authors.lastname: Kong
authors.forename: Udayan
authors.initials: U
authors.lastname: Apte
authors.forename: Grace
authors.initials: G
authors.lastname: Guo
authors.forename: Wen-Xing
authors.initials: WX
authors.lastname: Ding
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D001647:Bile Acids and Salts / Q000378:metabolism* / Q000494:pharmacology; D002401:Cathepsin B / Q000378:metabolism; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D002401:Cathepsin B; D008869:Microtubule-Associated Proteins; D046988:Proteasome Endopeptidase Complex; D018160:Receptors, Cytoplasmic and Nuclear; D051758:Transcription Factor TFIIH; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C490981:Gtf2h1 protein, mouse; C480860:Map1lc3b protein, mouse
keywords: autophagy; bile acid; farnesoid X receptor.; hepatocytes