Elevated hepatic DPP4 activity promotes insulin resistance and non-alcoholic fatty liver disease
| العنوان: | Elevated hepatic DPP4 activity promotes insulin resistance and non-alcoholic fatty liver disease |
|---|---|
| المؤلفون: | 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 |
| المصدر: | Molecular Metabolism Mol. Metab. 6, 1254-1263 (2017) Molecular Metabolism, Vol 6, Iss 10, Pp 1254-1263 (2017) |
| بيانات النشر: | Elsevier BV, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 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 |
| الوصف: | 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. |
| وصف الملف: | application/pdf |
| تدمد: | 2212-8778 |
| DOI: | 10.1016/j.molmet.2017.07.016 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ec108ccaaae2e081b54e4ea79fe8b459Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....ec108ccaaae2e081b54e4ea79fe8b459 |
| قاعدة البيانات: | OpenAIRE |
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fieldCode="DE" term="%22Steatosis%22">Steatosis</searchLink><br /><searchLink fieldCode="DE" term="%22GLP-1%22">GLP-1</searchLink><br /><searchLink fieldCode="DE" term="%22MCP1%2C+chemokine+%28C-C+motif%29+ligand+2%22">MCP1, chemokine (C-C motif) ligand 2</searchLink><br /><searchLink fieldCode="DE" term="%22MAPK%2C+mitogen-activated+protein+kinase%22">MAPK, mitogen-activated protein kinase</searchLink> ) Array ( [Name] => Abstract [Label] => Description [Group] => Ab [Data] => 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.<br />Graphical abstract Image 1<br />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. ) Array ( [Name] => Format [Label] => File Description [Group] => SrcInfo [Data] => application/pdf ) Array ( [Name] => ISSN [Label] => ISSN [Group] => ISSN [Data] => 2212-8778 ) Array ( [Name] => DOI [Label] => DOI [Group] => ID [Data] => 10.1016/j.molmet.2017.07.016 ) Array ( [Name] => URL [Label] => Access URL [Group] => URL [Data] => <link linkTarget="URL" linkTerm="https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ec108ccaaae2e081b54e4ea79fe8b459" linkWindow="_blank">https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ec108ccaaae2e081b54e4ea79fe8b459</link> ) Array ( [Name] => Copyright [Label] => Rights [Group] => Cpyrght [Data] => OPEN ) Array ( [Name] => AN [Label] => Accession Number [Group] => ID [Data] => edsair.doi.dedup.....ec108ccaaae2e081b54e4ea79fe8b459 ) |
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[SubjectFull] => WT, wild-type
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[SubjectFull] => BAT, brown adipose tissue
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[SubjectFull] => Steatosis
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(
[SubjectFull] => GLP-1
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(
[SubjectFull] => MCP1, chemokine (C-C motif) ligand 2
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|
| IllustrationInfo |