# Aryl hydrocarbon receptor-mediated differential gene regulation - Mechanism of stanniocalcin 2 mediated protection against NAFLD

> **NIH NIH R01** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2024 · $315,375

## Abstract

ABSTRACT
The Aryl Hydrocarbon Receptor (AhR) is a member of the Per-Arnt-Sim (PAS) domain protein family that
regulates adaptive and toxic responses to a variety of chemical pollutants, including polycyclic aromatic
hydrocarbons and halogenated aromatic hydrocarbons, most notably 2,3,7,8-tetrachlorodibenzo-p-dioxin
(TCDD). We observed that the newly identified endogenous AhR agonist, cinnabarinic acid (CA) does not
upregulate prototypical AhR target gene, Cyp1a1 and is not involved in xenobiotic regulation. On contrary, CA
induced expression of a novel AhR target gene, stanniocalcin 2 (Stc2) in liver. Our studies indicate that in
response to CA-treatment, AhR interacted dichotomously to xenobiotic response elements (XREs, 5'-GCGTG-
3') present within the Stc2 promoter regulating its expression. Additionally, this proposal capitalizes on our
recent observation that CA treatment protected against non-alcoholic fatty liver disease in an AhR-dependent
manner. The in vitro model that mimics fatty liver disease, showed significant role of STC2 in CA-specific AhR-
driven hepatoprotection. Moreover, we recently constructed hepatocyte-specific Stc2 conditional knockout
mice (Stc2-hKO) which showed exacerbated hepatic steatosis and metabolic deterioration. The studies
proposed in this renewal application are logical extension of our current award and hypothesize that the CA-
specific AhR-regulated hepatic STC2 signaling plays critical role in attenuation of lipogenesis resulting in
protection against non-alcoholic fatty liver disease. Using the Stc2-hKO mice, Specific Aim 1 of this application
will investigate role of in vivo STC2 signaling in AhR-mediated protection against steatohepatitis in response to
CA treatment. Specific Aim 2 will utilize lipidomics and single-nuclei transcriptomics to characterize CA-specific
STC2 mediated hepatoprotective pathways involved in the mitigation of lipogenesis. Specific Aim 3 will
investigate AhR-mediated regulation of Stc2 promoter in non-alcoholic fatty liver disease. The current
application will unravel mechanism of transcription regulation of Stc2 by CA-specific AhR activation and
characterize its significance against non-alcoholic fatty liver disease.

## Key facts

- **NIH application ID:** 10800156
- **Project number:** 2R01DK122028-07
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** Aditya D Joshi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $315,375
- **Award type:** 2
- **Project period:** 2019-07-12 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10800156

## Citation

> US National Institutes of Health, RePORTER application 10800156, Aryl hydrocarbon receptor-mediated differential gene regulation - Mechanism of stanniocalcin 2 mediated protection against NAFLD (2R01DK122028-07). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10800156. Licensed CC0.

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