Decrease of microRNA-122 causes hepatic insulin resistance by inducing protein tyrosine phosphatase 1B, which is reversed by licorice flavonoid

Abstract

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 0 -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 cJun 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 4a (HNF4a) responsible for miR-122 expression, as verified by the lack of HNF4a binding to the gene promoter. The regulatory role of JNK1 in PTP1B induction by a decrease in miR-122 level was strengthened by cellbased 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. Conclusion: Decreased levels of miR-122 as a consequence of HNF4a phosphorylation by JNK1 lead to hepatic insulin resistance through PTP1B induction, which may be overcome by chemical inhibition of JNK. (HEPATOLOGY 2012;56:2209-2220

Application of microRNAs in diabetes mellitus

“…Interestingly, some chemical compounds, e.g. licorice flavonoids and linoleic acid, regulated miRNAs and attenuated the pathogenesis of diabetes (Parra et al 2010, Yang et al 2012. The development of chemical compounds to regulate miRNAs implicated in diabetes could be another potential strategy to manipulate diabetes.…”

“…Protein tyrosine phosphatase 1B (PTP1B), a target of miR-122, inhibits hepatic insulin signaling by dephosphorylating tyrosine residues in the insulin receptor (IR) and IRS. A high-fat diet induces the phosphorylation of JUNK1 in mice, and decreases the expression of miR-122, resulting in an increase in hepatic insulin resistance (Yang et al 2012). Another study has shown that the reduction in miR-200a/b/c in the livers of db/db mice is associated with the inactivation of the AKT/GSK signaling pathway.…”

“…A decrease in miR-122 led to hepatic insulin resistance, while licorice flavonoids had been shown to reduce obesity-induced insulin resistance (Yang et al 2012). Joven et al (2012) showed that plantderived polyphenols could regulate the expression of miRNA paralogs, miR-103/-107 and miR-122, and prevent diet-induced fatty liver disease in hyperlipidemic mice.…”

miRNAs link metabolic reprogramming to oncogenesis

“…Protein tyrosine phosphatase 1B (PTP1B), a target of miR-122, inhibits hepatic insulin signaling by dephosphorylating insulin receptor and IRS. In high-fat-diet-fed mice and hepatocyte models with insulin resistance, the expression of miR-122 is downregulated [71].…”

Mining of single nucleotide polymorphisms in the 3' untranslated region of liver cancer-implicated miR-122 target genes

“…Currently there has been a lot of focus on the microRNA (miR)-122 to understand the genetics of hepatocellular carcinoma (HCC), pathology of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, hepatic insulin resistance, and lipid metabolism (1)(2)(3)(4). Interestingly, miR-122 expression levels were significantly reduced than the normal levels in HBV-associated liver cancer, but not in HCV related liver cancer (5).…”