title: Aryl hydrocarbon receptor-dependent stanniocalcin 2 induction by cinnabarinic acid provides cytoprotection against endoplasmic reticulum and oxidative stress.
abstract: The aryl hydrocarbon receptor (AhR) is a cytosolic ligand-activated transcription factor historically known for its role in xenobiotic metabolism. Although AhR activity has previously been shown to play a cytoprotective role against intrinsic apoptotic stimuli, the underlying mechanism by which AhR confers cytoprotection against apoptosis is largely unknown. Here, we demonstrate that activation of AhR by the tryptophan catabolite cinnabarinic acid (CA) directly upregulates expression of stanniocalcin 2 (Stc2) to elicit cytoprotection against apoptosis induced by endoplasmic reticulum stress and oxidative stress. Chromatin immunoprecipitation studies demonstrated that CA treatment induces direct AhR binding to a region of the Stc2 promoter containing multiple xenobiotic response elements. Using isolated primary hepatocytes from AhR wild-type (AhR floxed) and liver-specific AhR conditional knockout mice, we showed that pretreatment with CA conferred cytoprotection against hydrogen peroxide (H(2)O(2))-, thapsigargin-, and ethanol-induced apoptosis in an AhR-dependent manner. Furthermore, suppressing Stc2 expression using RNA interference confirmed that the cytoprotective properties of CA against H(2)O(2), thapsigargin, and ethanol injury were absolutely dependent on Stc2. Immunochemistry revealed the presence of Stc2 in the endoplasmic reticulum and on the cell surface, consistent with Stc2 secretion and autocrine and/or paracrine signaling. Finally, in vivo data using a mouse model of acute alcohol hepatotoxicity demonstrated that CA provided cytoprotection against ethanol-induced apoptosis, hepatic microvesicular steatosis, and liver injury. Collectively, our data uncovered a novel mechanism for AhR-mediated cytoprotection in the liver that is dependent on CA-induced Stc2 activity.
authors: Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (A.D.J., D.E.C., C.J.E.); and Linus Pauling Institute, Oregon State University, Corvallis, Oregon (T.A.H.).
authors: Aditya D
authors: AD
authors: Joshi
authors: Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (A.D.J., D.E.C., C.J.E.); and Linus Pauling Institute, Oregon State University, Corvallis, Oregon (T.A.H.).
authors: Dwayne E
authors: DE
authors: Carter
authors: Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (A.D.J., D.E.C., C.J.E.); and Linus Pauling Institute, Oregon State University, Corvallis, Oregon (T.A.H.).
authors: Tod A
authors: TA
authors: Harper
authors: Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (A.D.J., D.E.C., C.J.E.); and Linus Pauling Institute, Oregon State University, Corvallis, Oregon (T.A.H.) coelferi@utmb.edu.
authors: Cornelis J
authors: CJ
authors: Elferink
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D019610:Cytoprotection; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D000431:Ethanol / Q000494:pharmacology; D006023:Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D006861:Hydrogen Peroxide / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D018345:Mice, Knockout; D010078:Oxazines / Q000378:metabolism / Q000494:pharmacology*; D018384:Oxidative Stress; D011401:Promoter Regions, Genetic; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D019284:Thapsigargin / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010078:Oxazines; D018336:Receptors, Aryl Hydrocarbon; C485438:Stc2 protein, mouse; D000431:Ethanol; C000483:cinnabarinic acid; D019284:Thapsigargin; D006861:Hydrogen Peroxide