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- Title
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.
- Authors
Qiu, Wei; Avramoglu, Rita Kohen; Dubé, Nadia; Chong, Taryne M.; Naples, Mark; Au, Crystal; Sidiropoulos, Konstantinos G.; Lewis, Gary F.; Cohn, Jeffrey S.; Tremblay, Michel L.; Adeli, Khosrow; Dubé, Nadia
- 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.
- Subjects
PROTEIN-tyrosine phosphatase; INSULIN; CELLULAR signal transduction; INSULIN resistance; LIPOPROTEINS
- Publication
Diabetes, 2004, Vol 53, Issue 12, p3057
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/diabetes.53.12.3057