College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea.
Hepatology. 2012 Dec;56(6):2209-20. doi: 10.1002/hep.25912.
Protein tyrosine phosphatase 1B (PTP1B) inhibits hepatic insulin signaling by dephosphorylating tyrosine residues in insulin receptor (IR) and insulin receptor substrate (IRS). MicroRNAs may modulate metabolic functions. In view of the lack of understanding of the regulatory mechanism of PTP1B and its chemical inhibitors, this study investigated whether dysregulation of specific microRNA causes PTP1B-mediated hepatic insulin resistance, and if so, what the underlying basis is. In high-fat-diet-fed mice or hepatocyte models with insulin resistance, the expression of microRNA-122 (miR-122), the most abundant microRNA in the liver, was substantially down-regulated among those predicted to interact with the 3'-untranslated region of PTP1B messenger RNA (mRNA). Experiments using miR-122 mimic and its inhibitor indicated that miR-122 repression caused PTP1B induction. Overexpression of c-Jun N-terminal kinase 1 (JNK1) resulted in miR-122 down-regulation with the induction of PTP1B. A dominant-negative mutant of JNK1 had the opposite effect. JNK1 facilitated inactivating phosphorylation of hepatocyte nuclear factor 4α (HNF4α) responsible for miR-122 expression, as verified by the lack of HNF4α binding to the gene promoter. The regulatory role of JNK1 in PTP1B induction by a decrease in miR-122 level was strengthened by cell-based assays using isoliquiritigenin and liquiritigenin (components in Glycyrrhizae radix) as functional JNK inhibitors; JNK inhibition enabled cells to restore IR and IRS1/2 tyrosine phosphorylation and insulin signaling against tumor necrosis factor alpha, and prevented PTP1B induction. Moreover, treatment with each of the agents increased miR-122 levels and abrogated hepatic insulin resistance in mice fed a high-fat diet, causing a glucose-lowering effect.
Decreased levels of miR-122 as a consequence of HNF4α phosphorylation by JNK1 lead to hepatic insulin resistance through PTP1B induction, which may be overcome by chemical inhibition of JNK.
蛋白酪氨酸磷酸酶 1B（PTP1B）通过去磷酸化胰岛素受体（IR）和胰岛素受体底物（IRS）中的酪氨酸残基来抑制肝胰岛素信号。 microRNAs 可能调节代谢功能。鉴于对 PTP1B 及其化学抑制剂的调节机制缺乏了解，本研究调查了特定 microRNA 的失调是否会导致 PTP1B 介导的肝胰岛素抵抗，如果是这样，其潜在基础是什么。在高脂肪饮食喂养的小鼠或胰岛素抵抗的肝细胞模型中，预测与 PTP1B mRNA（信使 RNA）的 3'-非翻译区相互作用的 microRNA-122（miR-122）的表达显著下调，肝脏中最丰富的 microRNA。使用 miR-122 模拟物及其抑制剂的实验表明，miR-122 抑制导致 PTP1B 诱导。 c-Jun N 末端激酶 1（JNK1）的过表达导致 miR-122 下调并诱导 PTP1B。 JNK1 的显性负突变体则产生相反的效果。 JNK1 促进负责 miR-122 表达的肝细胞核因子 4α（HNF4α）的失活磷酸化，如通过缺乏 HNF4α 与基因启动子结合来验证。通过使用异甘草素和甘草素（甘草根的成分）作为功能性 JNK 抑制剂的基于细胞的测定，加强了 JNK1 在由 miR-122 水平降低引起的 PTP1B 诱导中的调节作用； JNK 抑制使细胞能够恢复 IR 和 IRS1/2 酪氨酸磷酸化和胰岛素信号转导对抗肿瘤坏死因子-α，并防止 PTP1B 诱导。此外，每种药物的治疗均增加了 miR-122 水平并在高脂肪饮食喂养的小鼠中消除了肝胰岛素抵抗，导致降低血糖作用。
由于 JNK1 对 HNF4α 的磷酸化，miR-122 水平降低导致肝胰岛素抵抗，通过化学抑制 JNK 可以克服这一问题。
