title: Regulation of Angiopoietin-Like Proteins (ANGPTLs) 3 and 8 by Insulin.
abstract: OBJECTIVE
  Circulating ANGPTL8 has recently been used as a marker of insulin action. We studied expression and insulin regulation of ANGPTL8 and ANGPTL3 in vivo and in vitro.
  
  
  METHODS
  Expression of ANGPTL8 and ANGPTL3 was studied in 34 paired samples of human liver and adipose tissue. Effects of insulin on 1) plasma concentrations and adipose tissue expression of ANGPTL8 and ANGPTL3 (in vivo 6-h euglycemic hyperinsulinemia; n = 18), and 2) ANGPTL8 and ANGPTL3 gene and protein expression in immortalized human hepatocytes (IHH) and adipocytes were measured. Effect of ANGPTL3 on secretion of ANGPTL8 in cells stably overexpressing ANGPTL3, -8, or both was determined.
  
  
  RESULTS
  ANGPTL3 was only expressed in the liver, whereas ANGPTL8 was expressed in both tissues. In vivo hyperinsulinemia significantly decreased both plasma ANGPTL8 and ANGPTL3 at 3 and 6 hours. Insulin increased ANGPTL8 expression in human adipose tissue 14- and 18-fold at 3 and 6 hours and ANGPTL8 was the most insulin-responsive transcript on microarray. Insulin also increased ANPGTL8 in cultured adipocytes and IHH but the protein mainly remained intracellular. In vitro in IHH, insulin decreased ANGPTL3 gene expression and secretion of ANGPTL3 into growth medium. Overexpression of ANGPTL8 in CHO cells did not result in its release into culture medium while abundant secretion occurred in cells co-expressing ANGPTL3 and -8.
  
  
  CONCLUSIONS
  Insulin decreases plasma ANGPTL3 by decreasing ANGPTL3 expression in the liver. Insulin markedly increases ANGPTL8 in adipose tissue and the liver but not in plasma. These data show that measurement of plasma ANGPTL3 but not -8 reflects insulin action in target tissues.
authors.affiliation: Minerva Foundation Institute for Medical Research (P.A.N.H., J.S., S.S., R.M., J.P., V.M.O., H.J.-J.), FI-00290 Helsinki, Finland; Public Health Genomics Unit (J.S., J.M., C.E., M.J.), National Institute for Health and Welfare, Helsinki, FI-00290 Helsinki, Finland; Department of Medicine (S.S.), FI-00014 University of Helsinki, Helsinki, Finland; Department of Internal Medicine (F.Q.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Haartman Institute (A.P., O.R.), FI-00014 University of Helsinki, FI-00029 Helsinki, Finland; Department of Surgery (M.L.), Helsinki University Central Hospital, University of Helsinki, FI-00029 Helsinki, Finland; Department of Biochemistry and Cancer Biology and Center for Diabetes and Endocrine Research (C.M.S.), University of Toledo College of Medicine, Toledo, Ohio 43614; Division of Paediatric Endocrinology and Diabetes, Department of Paediatrics and Adolescent Medicine (P.F.-P., M.W.), University of Ulm, D-89075 Ulm Germany.
authors.forename: P A
authors.initials: PA
authors.lastname: Nidhina Haridas
authors.affiliation: Minerva Foundation Institute for Medical Research (P.A.N.H., J.S., S.S., R.M., J.P., V.M.O., H.J.-J.), FI-00290 Helsinki, Finland; Public Health Genomics Unit (J.S., J.M., C.E., M.J.), National Institute for Health and Welfare, Helsinki, FI-00290 Helsinki, Finland; Department of Medicine (S.S.), FI-00014 University of Helsinki, Helsinki, Finland; Department of Internal Medicine (F.Q.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Haartman Institute (A.P., O.R.), FI-00014 University of Helsinki, FI-00029 Helsinki, Finland; Department of Surgery (M.L.), Helsinki University Central Hospital, University of Helsinki, FI-00029 Helsinki, Finland; Department of Biochemistry and Cancer Biology and Center for Diabetes and Endocrine Research (C.M.S.), University of Toledo College of Medicine, Toledo, Ohio 43614; Division of Paediatric Endocrinology and Diabetes, Department of Paediatrics and Adolescent Medicine (P.F.-P., M.W.), University of Ulm, D-89075 Ulm Germany.
authors.forename: Jarkko
authors.initials: J
authors.lastname: Soronen
authors.affiliation: Minerva Foundation Institute for Medical Research (P.A.N.H., J.S., S.S., R.M., J.P., V.M.O., H.J.-J.), FI-00290 Helsinki, Finland; Public Health Genomics Unit (J.S., J.M., C.E., M.J.), National Institute for Health and Welfare, Helsinki, FI-00290 Helsinki, Finland; Department of Medicine (S.S.), FI-00014 University of Helsinki, Helsinki, Finland; Department of Internal Medicine (F.Q.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Haartman Institute (A.P., O.R.), FI-00014 University of Helsinki, FI-00029 Helsinki, Finland; Department of Surgery (M.L.), Helsinki University Central Hospital, University of Helsinki, FI-00029 Helsinki, Finland; Department of Biochemistry and Cancer Biology and Center for Diabetes and Endocrine Research (C.M.S.), University of Toledo College of Medicine, Toledo, Ohio 43614; Division of Paediatric Endocrinology and Diabetes, Department of Paediatrics and Adolescent Medicine (P.F.-P., M.W.), University of Ulm, D-89075 Ulm Germany.
authors.forename: Sanja
authors.initials: S
authors.lastname: Sädevirta
authors.affiliation: Minerva Foundation Institute for Medical Research (P.A.N.H., J.S., S.S., R.M., J.P., V.M.O., H.J.-J.), FI-00290 Helsinki, Finland; Public Health Genomics Unit (J.S., J.M., C.E., M.J.), National Institute for Health and Welfare, Helsinki, FI-00290 Helsinki, Finland; Department of Medicine (S.S.), FI-00014 University of Helsinki, Helsinki, Finland; Department of Internal Medicine (F.Q.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Haartman Institute (A.P., O.R.), FI-00014 University of Helsinki, FI-00029 Helsinki, Finland; Department of Surgery (M.L.), Helsinki University Central Hospital, University of Helsinki, FI-00029 Helsinki, Finland; Department of Biochemistry and Cancer Biology and Center for Diabetes and Endocrine Research (C.M.S.), University of Toledo College of Medicine, Toledo, Ohio 43614; Division of Paediatric Endocrinology and Diabetes, Department of Paediatrics and Adolescent Medicine (P.F.-P., M.W.), University of Ulm, D-89075 Ulm Germany.
authors.forename: Raghavendra
authors.initials: R
authors.lastname: Mysore
authors.affiliation: Minerva Foundation Institute for Medical Research (P.A.N.H., J.S., S.S., R.M., J.P., V.M.O., H.J.-J.), FI-00290 Helsinki, Finland; Public Health Genomics Unit (J.S., J.M., C.E., M.J.), National Institute for Health and Welfare, Helsinki, FI-00290 Helsinki, Finland; Department of Medicine (S.S.), FI-00014 University of Helsinki, Helsinki, Finland; Department of Internal Medicine (F.Q.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Haartman Institute (A.P., O.R.), FI-00014 University of Helsinki, FI-00029 Helsinki, Finland; Department of Surgery (M.L.), Helsinki University Central Hospital, University of Helsinki, FI-00029 Helsinki, Finland; Department of Biochemistry and Cancer Biology and Center for Diabetes and Endocrine Research (C.M.S.), University of Toledo College of Medicine, Toledo, Ohio 43614; Division of Paediatric Endocrinology and Diabetes, Department of Paediatrics and Adolescent Medicine (P.F.-P., M.W.), University of Ulm, D-89075 Ulm Germany.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Quagliarini
authors.affiliation: Minerva Foundation Institute for Medical Research (P.A.N.H., J.S., S.S., R.M., J.P., V.M.O., H.J.-J.), FI-00290 Helsinki, Finland; Public Health Genomics Unit (J.S., J.M., C.E., M.J.), National Institute for Health and Welfare, Helsinki, FI-00290 Helsinki, Finland; Department of Medicine (S.S.), FI-00014 University of Helsinki, Helsinki, Finland; Department of Internal Medicine (F.Q.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Haartman Institute (A.P., O.R.), FI-00014 University of Helsinki, FI-00029 Helsinki, Finland; Department of Surgery (M.L.), Helsinki University Central Hospital, University of Helsinki, FI-00029 Helsinki, Finland; Department of Biochemistry and Cancer Biology and Center for Diabetes and Endocrine Research (C.M.S.), University of Toledo College of Medicine, Toledo, Ohio 43614; Division of Paediatric Endocrinology and Diabetes, Department of Paediatrics and Adolescent Medicine (P.F.-P., M.W.), University of Ulm, D-89075 Ulm Germany.
authors.forename: Arja
authors.initials: A
authors.lastname: Pasternack
authors.affiliation: Minerva Foundation Institute for Medical Research (P.A.N.H., J.S., S.S., R.M., J.P., V.M.O., H.J.-J.), FI-00290 Helsinki, Finland; Public Health Genomics Unit (J.S., J.M., C.E., M.J.), National Institute for Health and Welfare, Helsinki, FI-00290 Helsinki, Finland; Department of Medicine (S.S.), FI-00014 University of Helsinki, Helsinki, Finland; Department of Internal Medicine (F.Q.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Haartman Institute (A.P., O.R.), FI-00014 University of Helsinki, FI-00029 Helsinki, Finland; Department of Surgery (M.L.), Helsinki University Central Hospital, University of Helsinki, FI-00029 Helsinki, Finland; Department of Biochemistry and Cancer Biology and Center for Diabetes and Endocrine Research (C.M.S.), University of Toledo College of Medicine, Toledo, Ohio 43614; Division of Paediatric Endocrinology and Diabetes, Department of Paediatrics and Adolescent Medicine (P.F.-P., M.W.), University of Ulm, D-89075 Ulm Germany.
authors.forename: Jari
authors.initials: J
authors.lastname: Metso
authors.affiliation: Minerva Foundation Institute for Medical Research (P.A.N.H., J.S., S.S., R.M., J.P., V.M.O., H.J.-J.), FI-00290 Helsinki, Finland; Public Health Genomics Unit (J.S., J.M., C.E., M.J.), National Institute for Health and Welfare, Helsinki, FI-00290 Helsinki, Finland; Department of Medicine (S.S.), FI-00014 University of Helsinki, Helsinki, Finland; Department of Internal Medicine (F.Q.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Haartman Institute (A.P., O.R.), FI-00014 University of Helsinki, FI-00029 Helsinki, Finland; Department of Surgery (M.L.), Helsinki University Central Hospital, University of Helsinki, FI-00029 Helsinki, Finland; Department of Biochemistry and Cancer Biology and Center for Diabetes and Endocrine Research (C.M.S.), University of Toledo College of Medicine, Toledo, Ohio 43614; Division of Paediatric Endocrinology and Diabetes, Department of Paediatrics and Adolescent Medicine (P.F.-P., M.W.), University of Ulm, D-89075 Ulm Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Perttilä
authors.affiliation: Minerva Foundation Institute for Medical Research (P.A.N.H., J.S., S.S., R.M., J.P., V.M.O., H.J.-J.), FI-00290 Helsinki, Finland; Public Health Genomics Unit (J.S., J.M., C.E., M.J.), National Institute for Health and Welfare, Helsinki, FI-00290 Helsinki, Finland; Department of Medicine (S.S.), FI-00014 University of Helsinki, Helsinki, Finland; Department of Internal Medicine (F.Q.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Haartman Institute (A.P., O.R.), FI-00014 University of Helsinki, FI-00029 Helsinki, Finland; Department of Surgery (M.L.), Helsinki University Central Hospital, University of Helsinki, FI-00029 Helsinki, Finland; Department of Biochemistry and Cancer Biology and Center for Diabetes and Endocrine Research (C.M.S.), University of Toledo College of Medicine, Toledo, Ohio 43614; Division of Paediatric Endocrinology and Diabetes, Department of Paediatrics and Adolescent Medicine (P.F.-P., M.W.), University of Ulm, D-89075 Ulm Germany.
authors.forename: Marja
authors.initials: M
authors.lastname: Leivonen
authors.affiliation: Minerva Foundation Institute for Medical Research (P.A.N.H., J.S., S.S., R.M., J.P., V.M.O., H.J.-J.), FI-00290 Helsinki, Finland; Public Health Genomics Unit (J.S., J.M., C.E., M.J.), National Institute for Health and Welfare, Helsinki, FI-00290 Helsinki, Finland; Department of Medicine (S.S.), FI-00014 University of Helsinki, Helsinki, Finland; Department of Internal Medicine (F.Q.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Haartman Institute (A.P., O.R.), FI-00014 University of Helsinki, FI-00029 Helsinki, Finland; Department of Surgery (M.L.), Helsinki University Central Hospital, University of Helsinki, FI-00029 Helsinki, Finland; Department of Biochemistry and Cancer Biology and Center for Diabetes and Endocrine Research (C.M.S.), University of Toledo College of Medicine, Toledo, Ohio 43614; Division of Paediatric Endocrinology and Diabetes, Department of Paediatrics and Adolescent Medicine (P.F.-P., M.W.), University of Ulm, D-89075 Ulm Germany.
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Smas
authors.affiliation: Minerva Foundation Institute for Medical Research (P.A.N.H., J.S., S.S., R.M., J.P., V.M.O., H.J.-J.), FI-00290 Helsinki, Finland; Public Health Genomics Unit (J.S., J.M., C.E., M.J.), National Institute for Health and Welfare, Helsinki, FI-00290 Helsinki, Finland; Department of Medicine (S.S.), FI-00014 University of Helsinki, Helsinki, Finland; Department of Internal Medicine (F.Q.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Haartman Institute (A.P., O.R.), FI-00014 University of Helsinki, FI-00029 Helsinki, Finland; Department of Surgery (M.L.), Helsinki University Central Hospital, University of Helsinki, FI-00029 Helsinki, Finland; Department of Biochemistry and Cancer Biology and Center for Diabetes and Endocrine Research (C.M.S.), University of Toledo College of Medicine, Toledo, Ohio 43614; Division of Paediatric Endocrinology and Diabetes, Department of Paediatrics and Adolescent Medicine (P.F.-P., M.W.), University of Ulm, D-89075 Ulm Germany.
authors.forename: Pamela
authors.initials: P
authors.lastname: Fischer-Posovszky
authors.affiliation: Minerva Foundation Institute for Medical Research (P.A.N.H., J.S., S.S., R.M., J.P., V.M.O., H.J.-J.), FI-00290 Helsinki, Finland; Public Health Genomics Unit (J.S., J.M., C.E., M.J.), National Institute for Health and Welfare, Helsinki, FI-00290 Helsinki, Finland; Department of Medicine (S.S.), FI-00014 University of Helsinki, Helsinki, Finland; Department of Internal Medicine (F.Q.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Haartman Institute (A.P., O.R.), FI-00014 University of Helsinki, FI-00029 Helsinki, Finland; Department of Surgery (M.L.), Helsinki University Central Hospital, University of Helsinki, FI-00029 Helsinki, Finland; Department of Biochemistry and Cancer Biology and Center for Diabetes and Endocrine Research (C.M.S.), University of Toledo College of Medicine, Toledo, Ohio 43614; Division of Paediatric Endocrinology and Diabetes, Department of Paediatrics and Adolescent Medicine (P.F.-P., M.W.), University of Ulm, D-89075 Ulm Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Wabitsch
authors.affiliation: Minerva Foundation Institute for Medical Research (P.A.N.H., J.S., S.S., R.M., J.P., V.M.O., H.J.-J.), FI-00290 Helsinki, Finland; Public Health Genomics Unit (J.S., J.M., C.E., M.J.), National Institute for Health and Welfare, Helsinki, FI-00290 Helsinki, Finland; Department of Medicine (S.S.), FI-00014 University of Helsinki, Helsinki, Finland; Department of Internal Medicine (F.Q.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Haartman Institute (A.P., O.R.), FI-00014 University of Helsinki, FI-00029 Helsinki, Finland; Department of Surgery (M.L.), Helsinki University Central Hospital, University of Helsinki, FI-00029 Helsinki, Finland; Department of Biochemistry and Cancer Biology and Center for Diabetes and Endocrine Research (C.M.S.), University of Toledo College of Medicine, Toledo, Ohio 43614; Division of Paediatric Endocrinology and Diabetes, Department of Paediatrics and Adolescent Medicine (P.F.-P., M.W.), University of Ulm, D-89075 Ulm Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Ehnholm
authors.affiliation: Minerva Foundation Institute for Medical Research (P.A.N.H., J.S., S.S., R.M., J.P., V.M.O., H.J.-J.), FI-00290 Helsinki, Finland; Public Health Genomics Unit (J.S., J.M., C.E., M.J.), National Institute for Health and Welfare, Helsinki, FI-00290 Helsinki, Finland; Department of Medicine (S.S.), FI-00014 University of Helsinki, Helsinki, Finland; Department of Internal Medicine (F.Q.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Haartman Institute (A.P., O.R.), FI-00014 University of Helsinki, FI-00029 Helsinki, Finland; Department of Surgery (M.L.), Helsinki University Central Hospital, University of Helsinki, FI-00029 Helsinki, Finland; Department of Biochemistry and Cancer Biology and Center for Diabetes and Endocrine Research (C.M.S.), University of Toledo College of Medicine, Toledo, Ohio 43614; Division of Paediatric Endocrinology and Diabetes, Department of Paediatrics and Adolescent Medicine (P.F.-P., M.W.), University of Ulm, D-89075 Ulm Germany.
authors.forename: Olli
authors.initials: O
authors.lastname: Ritvos
authors.affiliation: Minerva Foundation Institute for Medical Research (P.A.N.H., J.S., S.S., R.M., J.P., V.M.O., H.J.-J.), FI-00290 Helsinki, Finland; Public Health Genomics Unit (J.S., J.M., C.E., M.J.), National Institute for Health and Welfare, Helsinki, FI-00290 Helsinki, Finland; Department of Medicine (S.S.), FI-00014 University of Helsinki, Helsinki, Finland; Department of Internal Medicine (F.Q.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Haartman Institute (A.P., O.R.), FI-00014 University of Helsinki, FI-00029 Helsinki, Finland; Department of Surgery (M.L.), Helsinki University Central Hospital, University of Helsinki, FI-00029 Helsinki, Finland; Department of Biochemistry and Cancer Biology and Center for Diabetes and Endocrine Research (C.M.S.), University of Toledo College of Medicine, Toledo, Ohio 43614; Division of Paediatric Endocrinology and Diabetes, Department of Paediatrics and Adolescent Medicine (P.F.-P., M.W.), University of Ulm, D-89075 Ulm Germany.
authors.forename: Matti
authors.initials: M
authors.lastname: Jauhiainen
authors.affiliation: Minerva Foundation Institute for Medical Research (P.A.N.H., J.S., S.S., R.M., J.P., V.M.O., H.J.-J.), FI-00290 Helsinki, Finland; Public Health Genomics Unit (J.S., J.M., C.E., M.J.), National Institute for Health and Welfare, Helsinki, FI-00290 Helsinki, Finland; Department of Medicine (S.S.), FI-00014 University of Helsinki, Helsinki, Finland; Department of Internal Medicine (F.Q.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Haartman Institute (A.P., O.R.), FI-00014 University of Helsinki, FI-00029 Helsinki, Finland; Department of Surgery (M.L.), Helsinki University Central Hospital, University of Helsinki, FI-00029 Helsinki, Finland; Department of Biochemistry and Cancer Biology and Center for Diabetes and Endocrine Research (C.M.S.), University of Toledo College of Medicine, Toledo, Ohio 43614; Division of Paediatric Endocrinology and Diabetes, Department of Paediatrics and Adolescent Medicine (P.F.-P., M.W.), University of Ulm, D-89075 Ulm Germany.
authors.forename: Vesa M
authors.initials: VM
authors.lastname: Olkkonen
authors.affiliation: Minerva Foundation Institute for Medical Research (P.A.N.H., J.S., S.S., R.M., J.P., V.M.O., H.J.-J.), FI-00290 Helsinki, Finland; Public Health Genomics Unit (J.S., J.M., C.E., M.J.), National Institute for Health and Welfare, Helsinki, FI-00290 Helsinki, Finland; Department of Medicine (S.S.), FI-00014 University of Helsinki, Helsinki, Finland; Department of Internal Medicine (F.Q.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Haartman Institute (A.P., O.R.), FI-00014 University of Helsinki, FI-00029 Helsinki, Finland; Department of Surgery (M.L.), Helsinki University Central Hospital, University of Helsinki, FI-00029 Helsinki, Finland; Department of Biochemistry and Cancer Biology and Center for Diabetes and Endocrine Research (C.M.S.), University of Toledo College of Medicine, Toledo, Ohio 43614; Division of Paediatric Endocrinology and Diabetes, Department of Paediatrics and Adolescent Medicine (P.F.-P., M.W.), University of Ulm, D-89075 Ulm Germany.
authors.forename: Hannele
authors.initials: H
authors.lastname: Yki-Järvinen
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects* / Q000378:metabolism; D000091303:Angiopoietin-Like Protein 3; D000091306:Angiopoietin-Like Protein 8; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D003412:Cricetulus; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D036361:Peptide Hormones / Q000235:genetics / Q000378:metabolism*
chemical_list: C479896:ANGPTL3 protein, human; C576683:ANGPTL8 protein, human; D000091303:Angiopoietin-Like Protein 3; D000091306:Angiopoietin-Like Protein 8; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; D007328:Insulin; D036361:Peptide Hormones