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 the 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 the 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 the 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 the endogenous AhR agonist, CA, confers hepatoprotection against
NAFLD by regulating hepatic
fatty acid uptake and lipogenesis. SIGNIFICANCE STATEMENT: In this study using in vitro and in vivo models, we demonstrate that
cinnabarinic acid (CA), an endogenous AhR agonist, provides protection against
non-alcoholic fatty liver disease. CA bestows cytoprotection against steatosis and liver injury by controlling expression of several key genes associated with lipid metabolism pathways, limiting the hepatic
lipid uptake, and controlling liver
inflammation. Moreover, CA-induced hepatoprotection is absolutely dependent on AhR and Stc2 expression.