title: Protein kinase Cδ but not PKCα is involved in insulin-induced glucose metabolism in hepatocytes.
abstract: The liver is a major insulin-responsive tissue responsible for glucose regulation. One important mechanism in this phenomenon is insulin-induced glycogen synthesis. Studies in our laboratory have shown that protein kinase Cs delta (PKCδ) and alpha (α) have important roles in insulin-induced glucose transport in skeletal muscle, and that their expression and activity are regulated by insulin. Their importance in glucose regulation in liver cells is unclear. In this study we investigated the possibility that these isoforms are involved in the mediation of insulin-induced glycogen synthesis in hepatocytes. Studies were done on rat hepatocytes in primary culture and on the AML-12 (alpha mouse liver) cell line. Insulin increased activity and tyrosine phosphorylation of PKCδ within 5 min. In contrast, activity and tyrosine phosphorylation of PKCα were not increased by insulin. PKCδ was constitutively associated with IR, and this was increased by insulin stimulation. Suppression of PKCδ expression by transfection with RNAi, or overexpression of kinase dead (dominant negative) PKCδ reduced both the insulin-induced activation of PKB/Akt and the phosphorylation of glycogen synthase kinase 3 (GSK3) and reduced significantly insulin-induced glucose uptake. In addition, treatment of primary rat hepatocytes with rottlerin abrogated insulin-induced increase in glycogen synthesis. Neither overexpression nor inhibition of PKCα appeared to alter activation of PKB, phosphorylation of GSK3 or glucose uptake in response to insulin. We conclude that PKCδ, but not PKCα, plays an essential role in insulin-induced glucose uptake and glycogenesis in hepatocytes.
authors.affiliation: Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
authors.forename: Tamar
authors.initials: T
authors.lastname: Brutman-Barazani
authors.forename: Miriam
authors.initials: M
authors.lastname: Horovitz-Fried
authors.forename: Shlomit
authors.initials: S
authors.lastname: Aga-Mizrachi
authors.forename: Chagit
authors.initials: C
authors.lastname: Brand
authors.forename: Chaya
authors.initials: C
authors.lastname: Brodie
authors.forename: Jagoda
authors.initials: J
authors.lastname: Rosa
authors.forename: Sanford R
authors.initials: SR
authors.lastname: Sampson
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism*; D006003:Glycogen / Q000096:biosynthesis; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism; D010766:Phosphorylation; D051571:Protein Kinase C-alpha / Q000235:genetics / Q000378:metabolism*; D051745:Protein Kinase C-delta / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction
chemical_list: D000098:Acetophenones; D001578:Benzopyrans; D007328:Insulin; D034741:RNA, Small Interfering; D006003:Glycogen; C085746:rottlerin; D051057:Proto-Oncogene Proteins c-akt; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D038362:Glycogen Synthase Kinase 3; D005947:Glucose