title: Hepatic very low density lipoprotein-ApoB overproduction is associated with attenuated hepatic insulin signaling and overexpression of protein-tyrosine phosphatase 1B in a fructose-fed hamster model of insulin resistance.
abstract: A fructose-fed hamster model of insulin resistance was previously documented to exhibit marked hepatic very low density lipoprotein (VLDL) overproduction. Here, we investigated whether VLDL overproduction was associated with down-regulation of hepatic insulin signaling and insulin resistance. Hepatocytes isolated from fructose-fed hamsters exhibited significantly reduced tyrosine phosphorylation of the insulin receptor and insulin receptor substrates 1 and 2. Phosphatidylinositol 3-kinase activity as well as insulin-stimulated Akt-Ser473 and Akt-Thr308 phosphorylation were also significantly reduced with fructose feeding. Interestingly, the protein mass and activity of protein-tyrosine phosphatase-1B (PTP-1B) were significantly higher in fructose-fed hamster hepatocytes. Chronic ex vivo exposure of control hamster hepatocytes to high insulin also appeared to attenuate insulin signaling and increase PTP-1B. Elevation in PTP-1B coincided with marked suppression of ER-60, a cysteine protease postulated to play a role in intracellular apoB degradation, and an increase in the synthesis and secretion of apoB. Sodium orthovanadate, a general phosphatase inhibitor, partially restored insulin receptor phosphorylation and significantly reduced apoB secretion. In summary, we hypothesize that fructose feeding induces hepatic insulin resistance at least in part via an increase in expression of PTP-1B. Induction of hepatic insulin resistance may then contribute to reduced apoB degradation and enhanced VLDL particle assembly and secretion.
authors.affiliation: Division of Clinical Biochemistry, Department of Laboratory Medicine and Pathobiology, Hospital for Sick Children, University of Toronto, Toronto, Ontario M5G 1X8, Canada.
authors.forename: Changiz
authors.initials: C
authors.lastname: Taghibiglou
authors.forename: Fariborz
authors.initials: F
authors.lastname: Rashid-Kolvear
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Van Iderstine
authors.forename: Hoang
authors.initials: H
authors.lastname: Le-Tien
authors.forename: I George
authors.initials: IG
authors.lastname: Fantus
authors.forename: Gary F
authors.initials: GF
authors.lastname: Lewis
authors.forename: Khosrow
authors.initials: K
authors.lastname: Adeli
mesh_terms: D000818:Animals; D001055:Apolipoproteins B / Q000096:biosynthesis*; D006224:Cricetinae; D003546:Cysteine Endopeptidases / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005632:Fructose; D007328:Insulin / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D047908:Intracellular Signaling Peptides and Proteins; D008079:Lipoproteins, VLDL / Q000096:biosynthesis*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008647:Mesocricetus; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011972:Receptor, Insulin / Q000378:metabolism; D014638:Vanadates / Q000494:pharmacology
chemical_list: D001055:Apolipoproteins B; D003546:Cysteine Endopeptidases; D005632:Fructose; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008079:Lipoproteins, VLDL; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011972:Receptor, Insulin; D014638:Vanadates; C077733:ER-60 protease