title: AKR1B7 is induced by the farnesoid X receptor and metabolizes bile acids.
abstract: Although bile acids are crucial for the absorption of lipophilic nutrients in the intestine, they are cytotoxic at high concentrations and can cause liver damage and promote colorectal carcinogenesis. The farnesoid X receptor (FXR), which is activated by bile acids and abundantly expressed in enterohepatic tissues, plays a crucial role in maintaining bile acids at safe concentrations. Here, we show that FXR induces expression of Akr1b7 (aldo-keto reductase 1b7) in murine small intestine, colon, and liver by binding directly to a response element in the Akr1b7 promoter. We further show that AKR1B7 metabolizes 3-keto bile acids to 3β-hydroxy bile acids that are less toxic to cultured cells than their 3α-hydroxy precursors. These findings reveal a feed-forward, protective pathway operative in murine enterohepatic tissues wherein FXR induces AKR1B7 to detoxify bile acids.
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Schmidt
authors.forename: Samuel
authors.initials: S
authors.lastname: Schmidt
authors.forename: Sam R
authors.initials: SR
authors.lastname: Holmstrom
authors.forename: Makoto
authors.initials: M
authors.lastname: Makishima
authors.forename: Ruth T
authors.initials: RT
authors.lastname: Yu
authors.forename: Carolyn L
authors.initials: CL
authors.lastname: Cummins
authors.forename: David J
authors.initials: DJ
authors.lastname: Mangelsdorf
authors.forename: Steven A
authors.initials: SA
authors.lastname: Kliewer
mesh_terms: D000449:Aldehyde Reductase / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D001647:Bile Acids and Salts / Q000235:genetics / Q000378:metabolism*; D003106:Colon / Q000201:enzymology*; D004790:Enzyme Induction / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D007421:Intestine, Small / Q000201:enzymology*; D008099:Liver / Q000201:enzymology*; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000502:physiology; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000449:Aldehyde Reductase; D001647:Bile Acids and Salts; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C066498:Akr1b7 protein, mouse