Elevated hepatic DPP4 activity promotes insulin resistance and non-alcoholic fatty liver disease
| Autor: | Thomas Laeger, Louise Fritsche, Christian Baumeier, Norbert Stefan, Annette Schürmann, Sophie Saussenthaler, Andreas Fritsche, Robert W. Schwenk, Maria Rödiger, Hans-Ulrich Häring, Luisa Schlüter, Stella Amelie Alaze |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male HFD high-fat diet PPARγ medicine.medical_treatment CD36 Adipose tissue AST aspartate aminotransferase SM skeletal muscle Mice F4/80 adhesion G protein-coupled receptor E1 GGT gamma-glutamyl transpeptidase Non-alcoholic Fatty Liver Disease Insulin rmDPP4 recombinant mouse dipeptidyl peptidase 4 rhDPP4 recombinant human dipeptidyl peptidase 4 Fatty liver Ad adenovirus sWAT subcutaneous white adipose tissue Hep G2 Cells Middle Aged Dgat2 diacylglycerol O-acyltransferase 2 Cd36 Dpp4 Glp-1 Insulin Resistance Nafld Pparγ TNFα tumor necrosis factor α Liver Cpt1a carnitine palmitoyltransferase 1a MOGAT1 monoacylglycerol O-acyltransferase 1 Original Article Female medicine.symptom PPARγ peroxisome proliferator activated receptor gamma Dpp4-Liv-Tg transgenic mice with hepatocyte-specific Dpp4 overexpression NFκB nuclear factor-κB Adult lcsh:Internal medicine medicine.medical_specialty NAFLD non-alcoholic fatty liver disease Akt Akt serine–threonine protein kinase HOMA-IR homeostatic model assessment for insulin resistance IL6 interleukin 6 NASH non-alcoholic steatohepatitis Dipeptidyl Peptidase 4 gWAT gonadal white adipose tissue Inflammation Srebf1 sterol regulatory element binding transcription factor 1 Mice Transgenic Biology DPP4 03 medical and health sciences Insulin resistance Internal medicine NAFLD ALT alanine aminotransferase medicine Animals Humans ApoB apolipoprotein B GLP-1 glucagon-like peptide 1 Obesity lcsh:RC31-1245 Molecular Biology pAkt phosphorylated Akt serine–threonine protein kinase Cell Biology medicine.disease CD36 fatty acid translocase DPP4 dipeptidyl peptidase 4 WT wild-type BAT brown adipose tissue Insulin receptor Disease Models Animal 030104 developmental biology Endocrinology biology.protein Hepatocytes Gfp green fluorescent protein Steatosis GLP-1 MCP1 chemokine (C-C motif) ligand 2 MAPK mitogen-activated protein kinase |
| Zdroj: | Molecular Metabolism Mol. Metab. 6, 1254-1263 (2017) Molecular Metabolism, Vol 6, Iss 10, Pp 1254-1263 (2017) |
| ISSN: | 2212-8778 |
| DOI: | 10.1016/j.molmet.2017.07.016 |
| Popis: | Objective Increased hepatic expression of dipeptidyl peptidase 4 (DPP4) is associated with non-alcoholic fatty liver disease (NAFLD). Whether this is causative for the development of NAFLD is not yet clarified. Here we investigate the effect of hepatic DPP4 overexpression on the development of liver steatosis in a mouse model of diet-induced obesity. Methods Plasma DPP4 activity of subjects with or without NAFLD was analyzed. Wild-type (WT) and liver-specific Dpp4 transgenic mice (Dpp4-Liv-Tg) were fed a high-fat diet and characterized for body weight, body composition, hepatic fat content and insulin sensitivity. In vitro experiments on HepG2 cells and primary mouse hepatocytes were conducted to validate cell autonomous effects of DPP4 on lipid storage and insulin sensitivity. Results Subjects suffering from insulin resistance and NAFLD show an increased plasma DPP4 activity when compared to healthy controls. Analysis of Dpp4-Liv-Tg mice revealed elevated systemic DPP4 activity and diminished active GLP-1 levels. They furthermore show increased body weight, fat mass, adipose tissue inflammation, hepatic steatosis, liver damage and hypercholesterolemia. These effects were accompanied by increased expression of PPARγ and CD36 as well as severe insulin resistance in the liver. In agreement, treatment of HepG2 cells and primary hepatocytes with physiological concentrations of DPP4 resulted in impaired insulin sensitivity independent of lipid content. Conclusions Our results give evidence that elevated expression of DPP4 in the liver promotes NAFLD and insulin resistance. This is linked to reduced levels of active GLP-1, but also to auto- and paracrine effects of DPP4 on hepatic insulin signaling. Graphical abstract Image 1 Highlights • NAFLD patients have augmented plasma DPP4 activity. • Hepatocyte-specific DPP4 overexpression in mice.(1)promotes fatty liver disease.(2)induces hepatic insulin resistance.(3)reduces systemic levels of active GLP-1.(4)enhances adipose tissue expansion and inflammation. |
| Databáze: | OpenAIRE |
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