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JNK1 phosphorylation of HNF4α represses miR‐122, which causes PTP1B induction
Author(s) -
Yang Yoon Mee,
Seo So Yeon,
Kim Tae Hyun,
Kim Sang Geon
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1169.9
Subject(s) - insulin resistance , phosphorylation , mir 122 , endocrinology , medicine , protein tyrosine phosphatase , chemistry , tyrosine phosphorylation , insulin , microrna , biology , microbiology and biotechnology , biochemistry , gene
MicroRNAs have emerged as key regulators of energy metabolism. The miR‐122 is the most abundant microRNA in the liver, and may affect cholesterol metabolism. Nevertheless, the role of miR‐122 in insulin sensitivity and blood glucose control had not been studied. This study investigated whether dysregulation of miR‐122 contributes to hepatic insulin resistance using animal and cell models. The levels of miR‐122 were down‐regulated in the liver of high‐fat diet (HFD)‐fed mice. miR‐122 was also repressed in hepatocytes treated with either TNFα or palmitate. We identified protein tyrosine phosphatase 1B (PTP1B), a key negative regulator of insulin signaling, as a novel target of miR‐122; decrease of miR‐122 caused PTP1B induction, as indicated by the results of miR‐122 mimic and its inhibitor experiments. JNK1 facilitated serine/threonine phosphorylation of HNF4α (i.e., HNF4α inhibition), which was responsible for miR‐122 down‐regulation in hepatocytes. Consistently, functional inhibition of JNK by licorice flavonoid treatment caused not only the restoration of miR‐122 levels, but also the repression of PTP1B. Moreover, JNK1 inhibition enabled cells to restore tyrosine‐phosphorylation of IR or IRS1/2, lowering blood glucose contents in HFD‐fed or ob/ob mice. In conclusion, miR‐122 dysregulation may increase insulin resistance through PTP1B induction, which depends on HNF4α phosphorylation by JNK1.