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

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.