Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, China.
Division of Regenerative Medicine and Therapeutics, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Sciences, Tottori University, Yonago, Japan.
Am J Physiol Endocrinol Metab. 2021 Jun 1;320(6):E1032-E1043. doi: 10.1152/ajpendo.00518.2020. Epub 2021 Apr 26.
Uric acid is the end metabolite derived from the oxidation of purine compounds. Overwhelming evidence shows the vital interrelationship between hyperuricemia (HUA) and nonalcoholic fatty liver disease (NAFLD). However, the mechanisms for this association remain unclear. In this study, we established a urate oxidase-knockout (Uox-KO) mouse model by clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 technology. To study the correlation between HUA and NAFLD, human HepG2 hepatoma cells were treated in culture medium with high level of uric acid. In vivo, the Uox-KO mice spontaneously developed hyperuricemia and aberrant lipid-metabolism, concomitant with abnormal hepatic fat accumulation. HUA activated c-Jun N-terminal kinase (JNK) in vivo and in vitro. Furthermore, inhibiting JNK activation by a JNK-specific inhibitor, SP600125, decreased fat accumulation and lipogenic gene expression induced by HUA. Overexpression of the lipogenic enzymes fatty acid synthase and acetyl-CoA carboxylase 1 was via activation of JNK, which was blocked by the JNK inhibitor SP600125. HUA activated AP-1 to upregulate lipogenic gene expression via JNK activation. In addition, HUA caused mitochondrial dysfunction and reactive oxygen species production. Pretreatment with the antioxidant -acetyl-l-cysteine could ameliorate HUA-activated JNK and hepatic steatosis. These data suggest that ROS/JNK/AP-1 signaling plays an important role in HUA-mediated fat accumulation in liver. Hyperuricemia and nonalcoholic fatty liver disease are global public health problems, which are strongly associated with metabolic syndrome. In this study, we demonstrate that uric acid induces hepatic fat accumulation via the ROS/JNK/AP-1 pathway. This study identifies a new mechanism of NAFLD pathogenesis and new potential therapeutic strategies for HUA-induced NAFLD.
尿酸是嘌呤化合物氧化的终末代谢产物。大量证据表明，高尿酸血症（HUA）与非酒精性脂肪性肝病（NAFLD）之间存在重要的相互关系。然而，这种关联的机制尚不清楚。在这项研究中，我们通过成簇规律间隔短回文重复（CRISPR）-Cas9 技术建立了尿酸氧化酶敲除（Uox-KO）小鼠模型。为了研究 HUA 与 NAFLD 之间的相关性，我们在含有高水平尿酸的培养基中培养人 HepG2 肝癌细胞。在体内，Uox-KO 小鼠自发地发展为高尿酸血症和异常脂质代谢，同时伴有异常的肝脂肪堆积。HUA 在体内和体外激活了 c-Jun N 端激酶（JNK）。此外，通过 JNK 特异性抑制剂 SP600125 抑制 JNK 激活，可减少 HUA 诱导的脂肪堆积和脂肪生成基因表达。脂肪酸合成酶和乙酰辅酶 A 羧化酶 1 的脂肪生成酶的过表达是通过 JNK 的激活，而 JNK 抑制剂 SP600125 可阻断这种激活。HUA 通过激活 AP-1 来上调脂肪生成基因的表达，从而激活 JNK。此外，HUA 还导致线粒体功能障碍和活性氧物质的产生。抗氧化剂 -乙酰-l-半胱氨酸预处理可改善 HUA 激活的 JNK 和肝脂肪变性。这些数据表明，ROS/JNK/AP-1 信号通路在 HUA 介导的肝脏脂肪堆积中发挥重要作用。高尿酸血症和非酒精性脂肪性肝病是全球性的公共卫生问题，与代谢综合征密切相关。在这项研究中，我们证明尿酸通过 ROS/JNK/AP-1 途径诱导肝脂肪堆积。本研究确定了 NAFLD 发病机制的新机制，并为 HUA 诱导的 NAFLD 提供了新的潜在治疗策略。
