Decoding Cinnabarinic Acid–Specific Stanniocalcin 2 Induction by Aryl Hydrocarbon Receptor

Patil, Nikhil Y.; Tang, Hui; Rus, Iulia; Zhang, Kangling; Joshi, Atul

doi:10.1124/molpharm.121.000376

Cited by 6 publications

(8 citation statements)

References 69 publications

(73 reference statements)

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“…Furthermore, the importance of nutrient metabolites such as acetyl coenzyme A (acetyl-CoA) and S-adenosylmethionine, which are acetyl and methyl donors for post-translational modifications (acetylation, methylation), is well known in epigenetic regulation. For instance, acetyl-CoA-specific histone H4 lysine 5 acetylation and histone H3 lysine 79 methylation at the AhR-bound stc2 promoter was recently reported [ 44 ], and we observed an increase in STC2 plasma concentration for individuals with ASD. Furthermore, KYN and 3-HK - the two KP metabolites for which a reliable concordance between peripheral and central measures was reported [ 45 ], and AA function as epigenetic modulators, increasing histone H3 lysine 4 trimethylation and histone H2A serine 40 O -glycosylation, resulting in up-regulated gene expression at most hypothalamic-linked loci [ 43 ].…”

Section: Discussionsupporting

confidence: 69%

Impact of IDO activation and alterations in the kynurenine pathway on hyperserotonemia, NAD+ production, and AhR activation in autism spectrum disorder

Launay,

Delorme,

Pagan

et al. 2023

Transl Psychiatry

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Hyperserotonemia is the most replicated biochemical anomaly associated with autism spectrum disorder (ASD) and has been reported in 35–46% of individuals with ASD. Serotonin is synthesised from the essential amino acid tryptophan (TRP). However, the main catabolic route of TRP is the kynurenine pathway (KP), which competes with serotonin synthesis when indoleamine dioxygenase (IDO) is activated. Using the same cohort of individuals with ASD, we used to report extensive studies of the serotonin/melatonin pathway, and found increased kynurenine (KYN), suggesting IDO activation in 58.7% of individuals with ASD (159/271), supported by a strong negative correlation between KYN/TRP ratio and miR-153-3p plasma levels, which negatively regulates IDO. IDO activation was associated with normoserotonemia, suggesting that IDO activation could mask hyperserotonemia which meant that hyperserotonemia, if not masked by IDO activation, could be present in ~94% of individuals with ASD. We also identified several KP alterations, independent of IDO status. We observed a decrease in the activity of 3-hydroxyanthranilate dioxygenase which translated into the accumulation of the aryl hydrocarbon receptor (AhR) selective ligand cinnabarinic acid, itself strongly positively correlated with the AhR target stanniocalcin 2. We also found a deficit in NAD+ production, the end-product of the KP, which was strongly correlated with plasma levels of oxytocin used as a stereotypical neuropeptide, indicating that regulated neuropeptide secretion could be limiting. These results strongly suggest that individuals with ASD exhibit low-grade chronic inflammation that is mediated in most cases by chronic AhR activation that could be associated with the highly prevalent gastrointestinal disorders observed in ASD, and explained IDO activation in ~58% of the cases. Taken together, these results extend biochemical anomalies of TRP catabolism to KP and posit TRP catabolism as a possible major component of ASD pathophysiology.

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Section: Discussionsupporting

confidence: 69%

Impact of IDO activation and alterations in the kynurenine pathway on hyperserotonemia, NAD+ production, and AhR activation in autism spectrum disorder

Launay,

Delorme,

Pagan

et al. 2023

Transl Psychiatry

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“…regimen elevated CA concentration in serum to ≈ 6000 pg/ml and resulted in 50% increase in a liver CA concentration (≈ 15 pg/mg) (Joshi et al, 2022). Our in vivo studies have observed activation of AhR and upregulation of Stc2 within 2 hr of 12 mg/kg CA treatment (Patil et al, 2022), and a daily CA administration was able to maintain an elevated Stc2 expression (Fig. S4A and C) (Joshi et al, 2022).…”

Section: Ca Regulates Lipid Metabolism In Vivomentioning

confidence: 70%

“…CA-induced steatoprotection is dependent on AhR-driven Stc2 signaling. CA is a known AhR agonist that specifically induce hepatic expression of an AhR target gene, Stc2 without Cyp1a1 upregulation (Patil et al, 2022). In HFD-fed mice livers, Stc2 expression was downregulated (Fig.…”

Section: Ca Regulates Lipid Metabolism In Vivomentioning

confidence: 98%

Cinnabarinic Acid Provides Hepatoprotection Against Nonalcoholic Fatty Liver Disease

Patil

Rus

Downing

et al. 2022

J Pharmacol Exp Ther

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Nonalcoholic fatty liver disease (NAFLD) is a chronic condition in which excess lipids accumulate in the liver and can lead to a range of progressive liver disorders including non-alcoholic steatohepatitis, liver cirrhosis, and hepatocellular carcinoma. While lifestyle and diet modifications have proven to be effective as NAFLD treatments, they are not sustainable in long-term and currently no pharmacological therapies are approved to treat NAFLD. Our previous studies demonstrated that cinnabarinic acid (CA), a novel endogenous Aryl hydrocarbon Receptor (AhR) agonist activates AhR target gene, Stanniocalcin 2 and confers cytoprotection against a plethora of ER/oxidative stressors. In this study, the hepatoprotective and anti-steatotic properties of CA were examined against free fatty acid-induced in vitro and high-fat diet-fed in vivo NAFLD models. The results demonstrated that CA treatment significantly lowered weight gain and attenuated hepatic lipotoxicity both before and after established fatty liver, thereby protecting against steatosis, inflammation and liver injury. CA mitigated intracellular free fatty acid uptake concomitant with the downregulation of CD36/fatty acid translocase. Genes involved in fatty acid and triglyceride synthesis were also downregulated in response to CA treatment. Additionally, suppressing AhR and Stc2 expression using RNA interference in vitro verified that the hepatoprotective effects of CA were absolutely dependent on both AhR and its target, Stc2. Collectively, our results demonstrate that endogenous AhR agonist, CA confers hepatoprotection against NAFLD by regulating hepatic fatty acid uptake and lipogenesis.

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“…We have identified endogenous AhR agonist, CA specific binding of chromatin modification ‘writers’ activating transcription factor 2 (Atf2), disruptor of telomeric silencing 1-like histone lysine methyltransferase (Dot1l) and ‘reader’ metastasis associated protein 2 (MTA2) to AhR at Stc2 promoter [ 101 , 119 ]. Cross-linking chromatin immunoprecipitation coupled mass spectrometry analysis detected CA-specific Atf2 driven histone H4 K5acetylation and Dot1l mediated H3 K79methylation exclusively at the Stc2 promoter [ 101 ]. These epigenetic modifications, which were observed in response to CA but not upon TCDD treatment, have been known to decrease DNA-histone interactions, open the chromatin structure and lead to the AhR-mediated transcription activation of Stc2 without Cyp1a1 induction [ 101 ].…”

Section: The Yin–yang Of Ahr Protection Against Nafld—a Conundrum!mentioning

confidence: 99%

“…Cross-linking chromatin immunoprecipitation coupled mass spectrometry analysis detected CA-specific Atf2 driven histone H4 K5acetylation and Dot1l mediated H3 K79methylation exclusively at the Stc2 promoter [ 101 ]. These epigenetic modifications, which were observed in response to CA but not upon TCDD treatment, have been known to decrease DNA-histone interactions, open the chromatin structure and lead to the AhR-mediated transcription activation of Stc2 without Cyp1a1 induction [ 101 ]. The CA-induced AhR-mediated Stc2 induction is thus protective against steatosis, inflammation and liver injury observed in NAFLD [ 97 ].…”

Section: The Yin–yang Of Ahr Protection Against Nafld—a Conundrum!mentioning

confidence: 99%

Role of Hepatic Aryl Hydrocarbon Receptor in Non-Alcoholic Fatty Liver Disease

2023

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Numerous nuclear receptors including farnesoid X receptor, liver X receptor, peroxisome proliferator-activated receptors, pregnane X receptor, hepatic nuclear factors have been extensively studied within the context of non-alcoholic fatty liver disease (NAFLD). Following the first description of the Aryl hydrocarbon Receptor (AhR) in the 1970s and decades of research which unveiled its role in toxicity and pathophysiological processes, the functional significance of AhR in NAFLD has not been completely decoded. Recently, multiple research groups have utilized a plethora of in vitro and in vivo models that mimic NAFLD pathology to investigate the functional significance of AhR in fatty liver disease. This review provides a comprehensive account of studies describing both the beneficial and possible detrimental role of AhR in NAFLD. A plausible reconciliation for the paradox indicating AhR as a ‘double-edged sword’ in NAFLD is discussed. Finally, understanding AhR ligands and their signaling in NAFLD will facilitate us to probe AhR as a potential drug target to design innovative therapeutics against NAFLD in the near future.

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Decoding Cinnabarinic Acid–Specific Stanniocalcin 2 Induction by Aryl Hydrocarbon Receptor

Cited by 6 publications

References 69 publications

Impact of IDO activation and alterations in the kynurenine pathway on hyperserotonemia, NAD+ production, and AhR activation in autism spectrum disorder

Impact of IDO activation and alterations in the kynurenine pathway on hyperserotonemia, NAD+ production, and AhR activation in autism spectrum disorder

Cinnabarinic Acid Provides Hepatoprotection Against Nonalcoholic Fatty Liver Disease

Role of Hepatic Aryl Hydrocarbon Receptor in Non-Alcoholic Fatty Liver Disease

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