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Hepatic DPP4 DNA methylation associates with fatty liver

Baumeier, Christian; Saussenthaler, Sophie; Kammel, Anne; Jähnert, Markus; Schlüter, Luisa; Hesse, Deike; Canouil, Mickaël; Lobbens, Stephane; Caiazzo, Robert and Raverdy, Violeta, et al. (2017) In Diabetes 66(1). p.25-35
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 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... (More)

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.

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published
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Diabetes
volume
66
issue
1
pages
11 pages
publisher
American Diabetes Association Inc.
external identifiers
  • scopus:85007320568
  • wos:000390834300008
ISSN
0012-1797
DOI
10.2337/db15-1716
language
English
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yes
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bc7b3079-07e6-4823-9ddb-da539fd95045
date added to LUP
2017-01-13 15:36:47
date last changed
2018-04-22 04:25:33
@article{bc7b3079-07e6-4823-9ddb-da539fd95045,
  abstract     = {<p>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.</p>},
  author       = {Baumeier, Christian and Saussenthaler, Sophie and Kammel, Anne and Jähnert, Markus and Schlüter, Luisa and Hesse, Deike and Canouil, Mickaël and Lobbens, Stephane and Caiazzo, Robert and Raverdy, Violeta and Pattou, François and Nilsson, Emma and Pihlajamäki, Jussi and Ling, Charlotte and Froguel, Philippe and Schürmann, Annette and Schwenk, Robert W.},
  issn         = {0012-1797},
  language     = {eng},
  month        = {01},
  number       = {1},
  pages        = {25--35},
  publisher    = {American Diabetes Association Inc.},
  series       = {Diabetes},
  title        = {Hepatic DPP4 DNA methylation associates with fatty liver},
  url          = {http://dx.doi.org/10.2337/db15-1716},
  volume       = {66},
  year         = {2017},
}