title: Dipeptidyl peptidase-4 impairs insulin signaling and promotes lipid accumulation in hepatocytes.
abstract: Dipeptidyl-peptidase 4 [DPP-4) has evolved into an important target in diabetes therapy due to its role in incretin hormone metabolism. In contrast to its systemic effects, cellular functions of membranous DPP-4 are less clear. Here we studied the role of DPP-4 in hepatic energy metabolism. In order to distinguish systemic from cellular effects we established a cell culture model of DPP-4 knockdown in human hepatoma cell line HepG2. DPP-4 suppression was associated with increased basal glycogen content due to enhanced insulin signaling as shown by increased phosphorylation of insulin-receptor substrate 1 (IRS-1), protein kinase B/Akt and mitogen-activated protein kinases (MAPK)/ERK, respectively. Additionally, glucose-6-phosphatase cDNA expression was significantly decreased in DPP-4 deficiency. Reduced triglyceride content in DPP-4 knockdown cells was paralleled by enhanced expressions of peroxisome proliferator-activated receptor alpha (PPARα) and carnitine palmitoyltransferase -1 (CPT-1) while sterol regulatory element-binding protein 1c (SREBP-1c) expression was significantly decreased. Our data suggest that hepatic DPP-4 induces a selective pathway of insulin resistance with reduced glycogen storage, enhanced glucose output and increased lipid accumulation in the liver. Hepatic DPP-4 might be a novel target in fatty liver disease in patients with glucose intolerance.
authors.affiliation: Christian Doppler Laboratory for Metabolic Crosstalk, Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria; Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Rufinatscha
authors.affiliation: Christian Doppler Laboratory for Metabolic Crosstalk, Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria; Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Radlinger
authors.affiliation: Christian Doppler Laboratory for Metabolic Crosstalk, Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria; Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Jochen
authors.initials: J
authors.lastname: Dobner
authors.affiliation: Christian Doppler Laboratory for Metabolic Crosstalk, Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria; Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Folie
authors.affiliation: Christian Doppler Laboratory for Metabolic Crosstalk, Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria; Clinica Medica 3, Padua University Hospital, Padua, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Bon
authors.affiliation: Christian Doppler Laboratory for Metabolic Crosstalk, Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria; Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Profanter
authors.affiliation: Christian Doppler Laboratory for Metabolic Crosstalk, Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria; Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Claudia
authors.initials: C
authors.lastname: Ress
authors.affiliation: Christian Doppler Laboratory for Metabolic Crosstalk, Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria; Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Karin
authors.initials: K
authors.lastname: Salzmann
authors.affiliation: Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Staudacher
authors.affiliation: Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Herbert
authors.initials: H
authors.lastname: Tilg
authors.affiliation: Christian Doppler Laboratory for Metabolic Crosstalk, Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria; Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria. Electronic address: susanne.kaser@i-med.ac.at.
authors.forename: Susanne
authors.initials: S
authors.lastname: Kaser
mesh_terms: D015153:Blotting, Western; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005947:Glucose / Q000378:metabolism; D005952:Glucose-6-Phosphatase / Q000235:genetics / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000235:genetics*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
chemical_list: D047493:PPAR alpha; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; D006003:Glycogen; D002334:Carnitine O-Palmitoyltransferase; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D005952:Glucose-6-Phosphatase; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D005947:Glucose
keywords: DPP4; Insulin resistance; Insulin signaling; Lipid metabolism; Liver