Hepatic DPP4 DNA Methylation Associates With Fatty Liver
Hepatic DPP4 DNA Methylation Associates With Fatty Liver
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DOI：
10.2337/db15-1716
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发表时间：
2017-01-01
期刊：
影响因子：
7.7
通讯作者：
Schwenk, Robert W.
中科院分区：
文献类型：
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作者：
Baumeier, Christian;Saussenthaler, Sophie;Schwenk, Robert W.
在肝脏中具有异位脂肪积聚的受试者中，肝脏DPP4表达升高。然而，是否增加二肽基肽酶4（DPP4）参与发病机制或代谢性疾病的后果尚不清楚。因此，我们研究了易患饮食诱导肥胖的年轻小鼠肝脏Dpp4的转录调控。在6周龄时，高体重增加的小鼠中肝脏Dpp4的表达增加，与肝脏脂肪含量无关。在相同的动物中，四个内含子CpG位点的甲基化降低，放大葡萄糖诱导的肝脏Dpp4转录。在老年小鼠中，肝脏甘油三酯含量仅在Dpp4表达升高的动物中增加。肝脏中DPP 4的表达和释放明显高于脂肪库。对人类肝活检标本的分析揭示了DPP4表达和DNA甲基化与脂肪肝和非酒精性脂肪性肝炎分期的相关性。总之，我们的研究结果表明肝脏在参与全身DPP4水平中起着至关重要的作用。此外，数据显示，葡萄糖诱导的Dpp4在肝脏中的表达是通过生命早期Dpp4基因的去甲基化来促进的。这可能导致肝功能的早期恶化，这反过来又导致代谢疾病，如肝脂肪变性。
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.