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.
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.
Qiu
Wei
W
Department of Laboratory Medicine and Pathobiology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
Avramoglu
Rita Kohen
RK
Dubé
Nadia
N
Chong
Taryne M
TM
Naples
Mark
M
Au
Crystal
C
Sidiropoulos
Konstantinos G
KG
Lewis
Gary F
GF
Cohn
Jeffrey S
JS
Tremblay
Michel L
ML
Adeli
Khosrow
K
D000818:Animals; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000096:biosynthesis / Q000097:blood* / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000097:blood; D022781:Hepatocytes / Q000201:enzymology / Q000502:physiology; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D016372:RNA, Antisense / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D012016:Reference Values; D014162:Transfection; D014280:Triglycerides / Q000097:blood
D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D016372:RNA, Antisense; D034741:RNA, Small Interfering; D014280:Triglycerides; D002784:Cholesterol; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; C516609:Ptpn1 protein, mouse