Aryl hydrocarbon receptor-dependent stanniocalcin 2 induction by cinnabarinic acid provides cytoprotection against endoplasmic reticulum and oxidative stress

Aditya D. Joshi, Dwayne E. Carter, Tod A. Harper, Cornelis Elferink

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)201-212
Number of pages12
JournalJournal of Pharmacology and Experimental Therapeutics
Volume353
Issue number1
DOIs
StatePublished - Apr 1 2015

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Aryl Hydrocarbon Receptors
Endoplasmic Reticulum Stress
Cytoprotection
Oxidative Stress
Apoptosis
Thapsigargin
Ethanol
Xenobiotics
Liver
Autocrine Communication
cinnabarinic acid
teleocalcin
Paracrine Communication
Immunochemistry
Chromatin Immunoprecipitation
Wounds and Injuries
Response Elements
Fatty Liver
RNA Interference
Knockout Mice

ASJC Scopus subject areas

  • Medicine(all)

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Aryl hydrocarbon receptor-dependent stanniocalcin 2 induction by cinnabarinic acid provides cytoprotection against endoplasmic reticulum and oxidative stress. / Joshi, Aditya D.; Carter, Dwayne E.; Harper, Tod A.; Elferink, Cornelis.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 353, No. 1, 01.04.2015, p. 201-212.

Research output: Contribution to journalArticle

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