title: Hepatic DPP4 DNA Methylation Associates With Fatty Liver.
abstract: Hepatic DPP4 expression is elevated in subjects with ectopic fat accumulation in the liver. However, whether increased dipeptidyl peptidase 4 (DPP4) is involved in the pathogenesis or is rather a consequence of metabolic disease is not known. We therefore studied the transcriptional regulation of hepatic Dpp4 in young mice prone to diet-induced obesity. Already at 6 weeks of age, expression of hepatic Dpp4 was increased in mice with high weight gain, independent of liver fat content. In the same animals, methylation of four intronic CpG sites was decreased, amplifying glucose-induced transcription of hepatic Dpp4 In older mice, hepatic triglyceride content was increased only in animals with elevated Dpp4 expression. Expression and release of DPP4 were markedly higher in the liver compared with adipose depots. Analysis of human liver biopsy specimens revealed a correlation of DPP4 expression and DNA methylation to stages of hepatosteatosis and nonalcoholic steatohepatitis. In summary, our results indicate a crucial role of the liver in participation to systemic DPP4 levels. Furthermore, the data show that glucose-induced expression of Dpp4 in the liver is facilitated by demethylation of the Dpp4 gene early in life. This might contribute to early deteriorations in hepatic function, which in turn result in metabolic disease such as hepatosteatosis later in life.
authors.affiliation: Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbrüecke, Nuthetal, Germany.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Baumeier
authors.affiliation: Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbrüecke, Nuthetal, Germany.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
authors.forename: Sophie
authors.initials: S
authors.lastname: Saussenthaler
authors.affiliation: Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbrüecke, Nuthetal, Germany.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Kammel
authors.affiliation: Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbrüecke, Nuthetal, Germany.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Jähnert
authors.affiliation: Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbrüecke, Nuthetal, Germany.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
authors.forename: Luisa
authors.initials: L
authors.lastname: Schlüter
authors.affiliation: Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbrüecke, Nuthetal, Germany.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
authors.forename: Deike
authors.initials: D
authors.lastname: Hesse
authors.affiliation: CNRS UMR 8199, Lille Pasteur Institute, Lille, France.|Lille 1 University, Lille, France.|European Genome Institute for Diabetes, Lille, France.
authors.forename: Mickaël
authors.initials: M
authors.lastname: Canouil
authors.affiliation: CNRS UMR 8199, Lille Pasteur Institute, Lille, France.|Lille 1 University, Lille, France.|European Genome Institute for Diabetes, Lille, France.
authors.forename: Stephane
authors.initials: S
authors.lastname: Lobbens
authors.affiliation: Lille 1 University, Lille, France.|European Genome Institute for Diabetes, Lille, France.|INSERM UMR 1190, CHU Lille, Lille, France.
authors.forename: Robert
authors.initials: R
authors.lastname: Caiazzo
authors.affiliation: Lille 1 University, Lille, France.|European Genome Institute for Diabetes, Lille, France.|INSERM UMR 1190, CHU Lille, Lille, France.
authors.forename: Violeta
authors.initials: V
authors.lastname: Raverdy
authors.affiliation: Lille 1 University, Lille, France.|European Genome Institute for Diabetes, Lille, France.|INSERM UMR 1190, CHU Lille, Lille, France.
authors.forename: François
authors.initials: F
authors.lastname: Pattou
authors.affiliation: Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Malmö, Sweden.
authors.forename: Emma
authors.initials: E
authors.lastname: Nilsson
authors.affiliation: Institute of Public Health and Clinical Nutrition, Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.|Clinical Nutrition and Obesity Center, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Jussi
authors.initials: J
authors.lastname: Pihlajamäki
authors.affiliation: Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Malmö, Sweden.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Ling
authors.affiliation: CNRS UMR 8199, Lille Pasteur Institute, Lille, France.|Lille 1 University, Lille, France.|European Genome Institute for Diabetes, Lille, France.|Department of Genomics of Common Disease, School of Public Health, Hammersmith Hospital, Imperial College London, London, U.K.
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
authors.affiliation: Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbrüecke, Nuthetal, Germany robert.schwenk@dife.de schuermann@dife.de.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Schürmann
authors.affiliation: Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbrüecke, Nuthetal, Germany robert.schwenk@dife.de schuermann@dife.de.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Schwenk
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics / Q000502:physiology; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics* / Q000378:metabolism*; D005234:Fatty Liver / Q000378:metabolism*; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
chemical_list: D014280:Triglycerides; D018819:Dipeptidyl Peptidase 4; D005947:Glucose