Prepl Controls Insulin Glucoregulatory Function in Liver by Transcriptional Targeting of SHP1 Tyrosine Phosphatase

摘要

Objective-we investigated the function of the prepl gene in insulin-dependent glucose homeostasis in liver. Research design and methods-prepl action on insulin glucoregulatory function has been analyzed in liver of prepi-hypomorphic mice (prep1~(i/i)), which express 2-3% of prepl mrna. Results-based on euglycemic hyperinsulinemic clamp studies and measurement of glycogen content, livers from prepl~(i/i) mice feature increased sensitivity to insulin. Tyrosine phosphor-ylation of both insulin receptor (ir) and insulin receptor substrate (irs)l/2 was significantly enhanced in prep1~(i/i) livers accompanied by a specific downregulation of the syp and shp1 tyrosine phosphatases. Prepl overexpression in hepg2 liver cells upregulated syp and shp1 and inhibited insulin-induced ir and irs1/2 phosphorylation and was accompanied by reduced glycogen content. Consistently, overexpression of the prepl partner pbxl, but not of pl60mbp, mimicked prepl effects on tyrosine phosphorylations, glycogen content, and on syp and shp1 expression. In prepl overexpressing cells, antisense silencing of shp1, but not that of syp, rescued insulin-dependent ir phosphorylation and glycogen accumulation. Both prepl and pbxl bind shp1 promoter at a site located between nucleotides -2,113 and -1,778. This fragment features enhancer activity and induces luciferase function by 7-, 6-, and 30-fold, respectively, in response to prepl, pbxl, or both. Conclusions-shp1, a known silencer of insulin signal, is a transcriptional target of prepl. In liver, transcriptional activation of shp1 gene by prepl attenuates insulin signal transduction and reduces glucose storage. Diabetes 60:138-147, 2011