Hepatic DPP4 expression is elevated in subjects with ectopic fat accumulation in the liver. However, it is not known if increased DPP4 is involved in the pathogenesis or rather a consequence of metabolic disease. Therefore, we 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 CpGs 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 liver compared to adipose depots. Analysis of human liver biopsies revealed a correlation of DPP4 expression and DNA-methylation to stages of hepatosteatosis and NASH. 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.
* Both authors contributed equally to this work
- Received December 17, 2016.
- Accepted September 25, 2016.
- © 2016 by the American Diabetes Association.