Hepatic DPP4 DNA methylation associates with fatty liver

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 ofmetabolic 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 glucoseinduced 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.

Saussenthaler, SophieGerman Center for Diabetes Research (författare)
Kammel, AnneGerman Center for Diabetes Research (författare)
Jähnert, MarkusGerman Center for Diabetes Research (författare)
Schlüter, LuisaGerman Center for Diabetes Research (författare)
Hesse, DeikeGerman Center for Diabetes Research (författare)
Canouil, MickaëlEuropean Genome Institute for Diabetes (EGID) UMR 8199 (författare)
Lobbens, StephaneEuropean Genome Institute for Diabetes (EGID) UMR 8199 (författare)
Caiazzo, RobertLille University Hospital (författare)
Raverdy, VioletaLille University Hospital (författare)
Pattou, FrançoisLille University Hospital (författare)
Nilsson, EmmaLund University,Lunds universitet,Celiaki och diabetes,Forskargrupper vid Lunds universitet,Celiac Disease and Diabetes Unit,Lund University Research Groups(Swepub:lu)med-e_n (författare)
Pihlajamäki, JussiKuopio University Hospital (författare)
Ling, CharlotteLund University,Lunds universitet,Diabetes - epigenetik,Forskargrupper vid Lunds universitet,Diabetes - Epigenetics,Lund University Research Groups(Swepub:lu)endo-cl0 (författare)
Froguel, PhilippeHammersmith Hospital (författare)
Schürmann, AnnetteGerman Center for Diabetes Research (författare)
Schwenk, Robert W.German Center for Diabetes Research (författare)
German Center for Diabetes ResearchEuropean Genome Institute for Diabetes (EGID) UMR 8199 (creator_code:org_t)

Av författaren/redakt...: Baumeier, Christ ...; Saussenthaler, S ...; Kammel, Anne; Jähnert, Markus; Schlüter, Luisa; Hesse, Deike; visa fler...; Canouil, Mickaël; Lobbens, Stephan ...; Caiazzo, Robert; Raverdy, Violeta; Pattou, François; Nilsson, Emma; Pihlajamäki, Jus ...; Ling, Charlotte; Froguel, Philipp ...; Schürmann, Annet ...; Schwenk, Robert ...; visa färre...

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MEDICIN OCH HÄLSOVETENSKAP: MEDICIN OCH HÄLS ...; och Klinisk medicin; och Gastroenterologi

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