Department of Pharmacology, Chung-Ang University, Seoul, Republic of Korea.
Department of Pathology, Chung-Ang University, Seoul, Republic of Korea.
J Cell Physiol. 2021 Jul;236(7):4902-4912. doi: 10.1002/jcp.30199. Epub 2020 Dec 7.
Endoplasmic reticulum (ER) stress plays a causative role in the development of nonalcoholic fatty liver disease (NAFLD). Kynurenic acid (KA) is a tryptophan metabolite that has been shown to exert anti-inflammatory effects in macrophages and endothelial cells. However, the role of KA in ER stress-associated development of NAFLD has not been fully explored. In the current study, we observed decreased KA levels in the serum of obese subjects. Treated hepatocytes with KA attenuated palmitate-induced lipid accumulation and downregulated lipogenesis-associated genes as well as ER stress markers in a dose-dependent manner. Furthermore, KA augmented AMP-activated protein kinase (AMPK) phosphorylation, oxygen-regulated protein 150 (ORP150) expression, and autophagy markers. The small interfering RNA-mediated suppression of AMPK and ORP150, or 3-methyladenine also abrogated the effects of KA on ER stress and lipid accumulation in hepatocytes. In accordance with in vitro observations, KA administration to mice fed a high-fat diet ameliorated hepatic lipid accumulation and decreased the expression of lipogenic genes as well as ER stress. Moreover, KA treatment increased hepatic AMPK phosphorylation, ORP150 expression, and autophagy related markers in mouse livers. Knockdown of AMPK using in vivo transfection mitigated the effects of KA on hepatic steatosis and ER stress as well as autophagy and ORP150 expression. These results suggest that KA ameliorates hepatic steatosis via the AMPK/autophagy- and AMPK/ORP150-mediated suppression of ER stress. In sum, KA might be used as a promising therapeutic agent for treatment of NAFLD.
内质网（ER）应激在非酒精性脂肪性肝病（NAFLD）的发展中起因果作用。犬尿氨酸（KA）是一种色氨酸代谢物，已被证明在巨噬细胞和内皮细胞中具有抗炎作用。然而，KA 在与 ER 应激相关的 NAFLD 发展中的作用尚未得到充分探索。在本研究中，我们观察到肥胖受试者血清中的 KA 水平降低。用 KA 处理肝细胞可剂量依赖性地减弱棕榈酸诱导的脂质积累，并下调脂肪生成相关基因以及 ER 应激标志物。此外，KA 增强了 AMP 激活的蛋白激酶（AMPK）磷酸化、氧调节蛋白 150（ORP150）表达和自噬标志物。用小干扰 RNA 抑制 AMPK 和 ORP150，或 3-甲基腺嘌呤也可消除 KA 对肝细胞 ER 应激和脂质积累的作用。与体外观察一致，KA 给药可改善高脂肪饮食喂养的小鼠的肝脂质积累，并降低脂肪生成基因以及 ER 应激的表达。此外，KA 处理可增加小鼠肝脏中 AMPK 磷酸化、ORP150 表达和自噬相关标志物。体内转染用 AMPK 敲低减轻了 KA 对肝脂肪变性和 ER 应激以及自噬和 ORP150 表达的影响。这些结果表明，KA 通过 AMPK/自噬和 AMPK/ORP150 介导的 ER 应激抑制来改善肝脂肪变性。总之，KA 可能被用作治疗 NAFLD 的有前途的治疗剂。
