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Diabetes 53:3057-3066, 2004
© 2004 by the American Diabetes Association, Inc.
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
1 Department of Laboratory Medicine and Pathobiology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
2 Department of Biochemistry and McGill Cancer Center, McGill University, Montreal, Quebec, Canada
3 Division of Endocrinology and Metabolism, University of Toronto, Toronto, Ontario, Canada
4 Clinical Research Institute of Montreal, Montreal, Quebec, Canada
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.
Address correspondencereprint requests to Khosrow Adeli, Division of Clinical Biochemistry, Hospital for Sick Children, 555 University Ave., Toronto, Ontario, Canada M5G 1X8. E-mail: k.adeli{at}utoronto.ca
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