School of Biological Sciences and Technology, Chonnam National University, Gwangju 61186, Republic of Korea.
School of Biological Sciences and Technology, Chonnam National University, Gwangju 61186, Republic of Korea.
Steroids. 2023 Jun;194:109226. doi: 10.1016/j.steroids.2023.109226. Epub 2023 Mar 21.
Lysyl oxidase (LOX), the copper-dependent extracellular enzyme, plays a critical role in the regulation of protein cross-linking in the extracellular matrix (ECM). It is also involved in liver regeneration and liver fibrosis. However, the mechanism of LOX regulation in mouse hepatocytes is still unclear. Here, we identify a molecular mechanism showing that orphan nuclear receptor estrogen-related receptor γ (ERRγ) regulates LOX gene expression in the presence of the pro-inflammatory cytokine, interleukin 6 (IL6). IL6 significantly stimulated the expression of ERRγ and LOX in mouse hepatocytes. Overexpression of ERRγ increased LOX mRNA and protein levels. Moreover, knockdown of ERRγ attenuated IL6-mediated LOX gene expression at mRNA and protein levels. Overexpression of ERRγ or IL6 treatment upregulated LOX gene promoter activity, while knockdown of ERRγ decreased the IL6-induced LOX promoter activity. Furthermore, GSK5182, a specific ERRγ inverse agonist, inhibited the induction effect of IL6 on LOX promoter activity and gene expression in mouse hepatocytes. Overall, our study elucidates the mechanism involved in the LOX gene regulation by nuclear receptor ERRγ in response to IL6 in mouse hepatocytes, suggesting that, in conditions such as chronic inflammation, IL6 may contribute to liver fibrosis via inducing LOX gene expression. Thus, LOX gene regulation by the inverse agonist of ERRγ can be applied to improve liver fibrosis.
赖氨酰氧化酶（LOX）是一种铜依赖性细胞外酶，在细胞外基质（ECM）中蛋白质交联的调节中发挥着关键作用。它还参与肝脏再生和肝纤维化。然而，LOX 在小鼠肝细胞中的调节机制尚不清楚。在这里，我们确定了一种分子机制，表明孤儿核受体雌激素相关受体 γ（ERRγ）在促炎细胞因子白细胞介素 6（IL6）存在的情况下调节 LOX 基因表达。IL6 显著刺激了小鼠肝细胞中 ERRγ 和 LOX 的表达。ERRγ 的过表达增加了 LOX mRNA 和蛋白水平。此外，ERRγ 的敲低减弱了 IL6 介导的 LOX 基因在 mRNA 和蛋白水平上的表达。过表达 ERRγ 或 IL6 处理上调了 LOX 基因启动子活性，而 ERRγ 的敲低降低了 IL6 诱导的 LOX 启动子活性。此外，GSK5182，一种特异性 ERRγ 反向激动剂，抑制了 IL6 在小鼠肝细胞中对 LOX 启动子活性和基因表达的诱导作用。总的来说，我们的研究阐明了核受体 ERRγ 响应 IL6 在小鼠肝细胞中调节 LOX 基因的机制，表明在慢性炎症等情况下，IL6 可能通过诱导 LOX 基因表达导致肝纤维化。因此，ERRγ 的反向激动剂对 LOX 基因的调节可应用于改善肝纤维化。
