Department of Pharmaceutical Sciences (N.Y.P., I.R., E.D., A.D.J.) and Harold Hamm Diabetes Center (A.M., J.E.F., A.D.J.), University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
J Pharmacol Exp Ther. 2022 Oct;383(1):32-43. doi: 10.1124/jpet.122.001301. Epub 2022 Aug 6.
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.
非酒精性脂肪性肝病（NAFLD）是一种慢性疾病，其特征是肝脏中过量的脂质积聚，并可能导致一系列进行性肝脏疾病，包括非酒精性脂肪性肝炎、肝硬化和肝细胞癌。虽然生活方式和饮食改变已被证明是治疗 NAFLD 的有效方法，但它们在长期内是不可持续的，目前尚无批准的药物疗法可用于治疗 NAFLD。我们之前的研究表明，肉桂酸（CA），一种新型内源性芳香烃受体（AhR）激动剂，可激活 AhR 靶基因，Stanniocalcin 2，并赋予细胞保护作用，对抗多种内质网/氧化应激源。在这项研究中，我们研究了 CA 对游离脂肪酸诱导的体外和高脂肪饮食喂养的体内 NAFLD 模型的肝保护和抗脂肪变性特性。结果表明，CA 治疗可显著降低体重增加，并在建立脂肪肝前后减轻肝毒性，从而防止脂肪变性、炎症和肝损伤。CA 减轻了细胞内游离脂肪酸的摄取，同时下调了 CD36/脂肪酸转运蛋白。CA 治疗还下调了参与脂肪酸和甘油三酯合成的基因。此外，在体外使用 RNA 干扰抑制 AhR 和 Stc2 表达证实，CA 的肝保护作用绝对依赖于 AhR 和其靶基因 Stc2。总之，我们的研究结果表明，内源性 AhR 激动剂 CA 通过调节肝脏脂肪酸摄取和脂肪生成，对 NAFLD 提供肝保护。
