Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, United States of America.
PLoS One. 2012;7(8):e43961. doi: 10.1371/journal.pone.0043961. Epub 2012 Aug 27.
Farnesoid X Receptor (FXR) is a member of the nuclear receptor superfamily and is a ligand-activated transcription factor essential for maintaining liver and intestinal homeostasis. FXR is protective against carcinogenesis and inflammation in liver and intestine as demonstrated by the development of inflammation and tumors in the liver and intestine of FXR knock-out mice. However, mechanisms for the protective effects of FXR are not completely understood. This study reports a novel role of FXR in regulating expression of Sqstm1, which encodes for p62 protein. p62 plays an important role in maintaining cellular homeostasis through selective autophagy and activating signal transduction pathways, such as NF-κB to support cell survival and caspase-8 to initiate apoptosis. FXR regulation of Sqstm1 may serve as a protective mechanism.
This study showed that FXR bound to the Sqstm1 gene in both mouse livers and ileums as determined by chromatin immunoprecipitation. In addition, FXR activation enhanced transcriptional activation of Sqstm1 in vitro. However, wild-type mice treated with GW4064, a synthetic FXR ligand, showed that FXR activation induced mRNA and protein expression of Sqstm1/p62 in ileum, but not in liver. Interestingly, FXR-transgenic mice showed induced mRNA expression of Sqstm1 in both liver and ileum compared to wild-type mice.
Our current study has identified a novel role of FXR in regulating the expression of p62, a key factor in protein degradation and cell signaling. Regulation of p62 by FXR indicates tissue-specific and gene-dosage effects. Furthermore, FXR-mediated induction of p62 may implicate a protective mechanism of FXR.
法尼醇 X 受体 (FXR) 是核受体超家族的成员，是维持肝脏和肠道内稳态所必需的配体激活转录因子。FXR 可防止肝脏和肠道发生癌变和炎症，FXR 敲除小鼠的肝脏和肠道中会出现炎症和肿瘤。然而，FXR 保护作用的机制尚不完全清楚。本研究报告了 FXR 调节 Sqstm1 表达的新作用，Sqstm1 编码 p62 蛋白。p62 通过选择性自噬和激活信号转导途径（如 NF-κB 以支持细胞存活和 caspase-8 以启动细胞凋亡）在维持细胞内稳态方面发挥重要作用。FXR 对 Sqstm1 的调节可能是一种保护机制。
本研究通过染色质免疫沉淀实验表明，FXR 在小鼠肝脏和回肠中均与 Sqstm1 基因结合。此外，FXR 激活增强了 Sqstm1 的体外转录激活。然而，用合成 FXR 配体 GW4064 处理野生型小鼠后，发现 FXR 激活诱导了回肠中 Sqstm1/p62 的 mRNA 和蛋白表达，但在肝脏中没有。有趣的是，与野生型小鼠相比，FXR 转基因小鼠在肝脏和回肠中均诱导 Sqstm1 的 mRNA 表达。
我们目前的研究确定了 FXR 在调节 p62（蛋白降解和细胞信号的关键因子）表达中的新作用。FXR 对 p62 的调节表明存在组织特异性和基因剂量效应。此外，FXR 介导的 p62 诱导可能暗示了 FXR 的一种保护机制。
