Cinnabarinic Acid Provides Hepatoprotection Against Nonalcoholic Fatty Liver Disease

Abstract

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.

A Review on the Role and Function of Cinnabarinic Acid, a “Forgotten” Metabolite of the Kynurenine Pathway

“…Joshi et al, in a series of papers, analyzed the cytoprotective effects of CA against apoptosis induced by endoplasmic reticulum stress, oxidative stress, and alcohol insult (acute and chronic) and in non-alcoholic fatty liver disease [ 86 , 87 , 95 , 97 ]. They revealed that the CA-driven cytoprotecting activity is associated with the activation of AhR.…”

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

“…CA treatment significantly lowered body mass gain and decreased hepatic steatosis both before and after the established NAFLD. CA decreased free fatty acid uptake by downregulation of Cd36 expression as well as attenuated lipogenesis [ 97 ]. CA- induced AhR was unable to interact with the Cyp1a1 promoter and therefore did not increase its expression in isolated primary hepatocytes or in vivo [ 1 , 98 ].…”

“…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 ]. (4) AhR signaling is also known to cross react with other signaling pathways involved in lipogenesis and oxidative metabolism.…”

The Ah Receptor from Toxicity to Therapeutics: Report from the 5th AHR Meeting at Penn State University, USA, June 2022

“…CA also has cytoprotection against steatosis and hepatic damage in an Stc2-dependent manner in alcoholic liver disease mouse models by modulating ERK1/2 activity. Overall, these studies underline the existence of a CA-AHR-STC2 signaling cascade relevant in those liver diseases [ 69 ].…”