PTP1B deficiency enhances liver growth during suckling by increasing the expression of insulin‐like growth factor‐I

Abstract

Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of insulin and tyrosine kinase growth factor signaling. We have recently demonstrated that PTP1B deficiency increases GLUT2/insulin receptor (IR) A complexes and glucose uptake in suckling, but not adult, primary hepatocytes. Herein we have investigated intrahepatic glucose utilization in 3-5 days old wild-type and PTP1B(-/-) mice. PTP1B deficiency decreased glycogen, lactate, and pyruvate content in the livers from suckling mice. Conversely, the activity of glucose 6-phosphate dehydrogenase (G6PD), the rate limiting enzyme of the pentose phosphate cycle (PPC) which provides substrates for DNA synthesis, was enhanced in the liver of PTP1B(-/-) animals. Liver weight, liver-to-body mass ratio, DNA content, and PCNA expression were increased in PTP1B(-/-) suckling mice compared to the wild-type controls. At the molecular level, STAT 5B phosphorylation, IGF-I mRNA, and protein levels as well as IGF-IR tyrosine phosphorylation were increased in the livers of PTP1B-deficient neonates. Unexpectedly, hepatic and serum triglycerides (TG) were increased by PTP1B deficiency, although the expression of lipogenic enzymes remained as in the wild-type controls. However, the analysis of milk composition revealed higher TG content in lactating females lacking PTP1B. The effects of PTP1B deficiency on G6PD activity, STAT 5B/IGF-I/IGF-IR axis, PCNA expression and liver growth during suckling were maintained by transferring PTP1B(-/-) embryos (PTP1B(-/-T)) to a wild-type female. Conversely, PTP1B(-/-T) mice did not show hepatic fat accumulation. In conclusion, the present study suggests that PTP1B plays a unique role in the control of the physiological liver development after birth.

Growth hormone STAT5-mediated signaling and its modulation in mice liver during the growth period

“…SHP1 and SHP2 present no age difference, while PTP1B content is elevated in one-week mice and decreases thereafter. Our results suggest that PTP1B could be participating in the rapid dephosphorylation of activated substrates at early ages, thus impeding GH signaling, in agreement with recent observations in which STAT5 phosphorylation was found augmented in PTP1B -/-3 day old mice [64], and that rapid STAT5 dephosphorylation was described when PTP1B was overexpressed [14]. Mice lacking functional SHP1, SHP2 or PTP1B do not present enhanced growth [65][66][67], while mice lacking the PTPH1 catalytic domain exhibit a modest increment in body weight, especially in male mice.…”

Dual role of protein tyrosine phosphatase 1B in the progression and reversion of non-alcoholic steatohepatitis

“…The molecular mechanism responsible of this effect likely involve tyrosine kinase receptors such as EGF receptor, HGF receptor (Met) or insulin-like growth factor-1 receptor (IGF1R), implicated in the control of proliferation and survival of hepatocytes, all of them dephosphorylated and inactivated by PTP1B [49] . In this regard, we have described that PTP1B deficiency increases liver growth enhancing the STAT5B/IGF1/IGF1R axis during suckling [50] . In addition, the faster recovery of PTP1BKO livers against NASH damage might also involve an effect on hepatic oval cells since their proliferation positively correlates with the extent of liver damage [51] .…”

Post-Receptor Inhibitors of the GHR-JAK2-STAT Pathway in the Growth Hormone Signal Transduction

“…Likewise other researchers conducted studies on the PTP-1B KO mice and observed significant growth disturbances. Escrivá et al [ 107 ] stated that PTP-1B KO mice had higher body and liver weight at the 3rd day after birth. The same authors showed that PTP-1B KO mice were characterized by the increased STAT5β phosphorylation and, in consequence, the increased level of the IGF-1 in liver was stated.…”