Hepatic PTP-1B expression regulates the assembly and secretion of apolipoprotein B-containing lipoproteins: evidence from protein tyrosine phosphatase-1B overexpression, knockout, and RNAi studies

Diabetes. 2004 Dec;53(12):3057-66. doi: 10.2337/diabetes.53.12.3057.

Abstract

Protein tyrosine phosphatase-1B (PTP-1B) plays an important role in regulation of insulin signal transduction, and modulation of PTP-1B expression seems to have a profound effect on insulin sensitivity and diet-induced weight gain. The molecular link between PTP-1B expression and metabolic dyslipidemia, a major complication of insulin resistance, was investigated in the present study using PTP-1B knockout mice as well as overexpression and suppression of PTP-1B. Chronic fructose feeding resulted in a significant increase in plasma VLDL in wild-type mice but not in PTP-1B knockout mice. Lipoprotein profile analysis of plasma from PTP-1B knockout mice revealed a significant reduction in apolipoprotein B (apoB100) lipoproteins, associated with reduced hepatic apoB100 secretion from isolated primary hepatocytes. In addition, treatment of cultured hepatoma cells with PTP-1B siRNA reduced PTP-1B mass by an average of 41% and was associated with a 53% decrease in secretion of metabolically labeled apoB100. Conversely, adenoviral-mediated overexpression of PTP-1B in HepG2 cells downregulated the phosphorylation of insulin receptor and insulin receptor substrate-1 and caused increases in cellular and secreted apoB100 as a result of increased intracellular apoB100 stability. Collectively, these findings suggest that PTP-1B expression level is a key determinant of hepatic lipoprotein secretion, and its overexpression in the liver can be sufficient to induce VLDL overproduction and the transition to a metabolic dyslipidemic state.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoprotein B-100
  • Apolipoproteins B / biosynthesis
  • Apolipoproteins B / blood*
  • Apolipoproteins B / metabolism*
  • Cell Line
  • Cell Line, Tumor
  • Cholesterol / blood
  • Hepatocytes / enzymology
  • Hepatocytes / physiology
  • Humans
  • Liver / enzymology
  • Liver / metabolism*
  • Mice
  • Mice, Knockout
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Protein Tyrosine Phosphatases / genetics*
  • RNA, Antisense / genetics*
  • RNA, Small Interfering / genetics
  • Reference Values
  • Transfection
  • Triglycerides / blood

Substances

  • Apolipoprotein B-100
  • Apolipoproteins B
  • RNA, Antisense
  • RNA, Small Interfering
  • Triglycerides
  • Cholesterol
  • PTPN1 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Protein Tyrosine Phosphatases
  • Ptpn1 protein, mouse