Epigenetic regulation of hepatic Dpp4 expression in response to dietary protein.
Epigenetic regulation of hepatic Dpp4 expression in response to dietary protein.
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DOI：
10.1016/j.jnutbio.2018.09.025
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发表时间：
2019
期刊：
影响因子：
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通讯作者：
S. Saussenthaler;M. Ouni;C. Baumeier;K. Schwerbel;P. Gottmann;S. Christmann;T. Laeger;A. Schürmann
中科院分区：
文献类型：
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作者：
S. Saussenthaler;M. Ouni;C. Baumeier;K. Schwerbel;P. Gottmann;S. Christmann;T. Laeger;A. Schürmann
已知二肽基肽酶4(DPP4)在肥胖、2型糖尿病和脂肪肝等代谢紊乱中升高。通过药物抑制降低DPP4浓度可改善血糖稳态，并显示出降低肝脏脂肪含量的有利作用。由于调控Dpp4内源性表达的因素尚不清楚，本研究的目的是检查Dpp4的表达是否受饮食成分的表观遗传调控。用不同的微量营养素处理原代肝细胞，检测Dpp4mRNA水平和DPP4活性。此外，对新西兰肥胖(NZO)小鼠进行了饮食低蛋白干预，随后测定了对Dpp4表达、甲基化以及血浆浓度和活性的影响。我们的结果表明，在几种组织中，Dpp4mRNA的表达是由DNA甲基化介导的。因此，我们认为Dpp4南岸是组织分化甲基化区域。氨基酸可增加原代肝细胞Dpp4的表达，而葡萄糖和脂肪酸对其无影响。限制饮食蛋白质增加肝脏Dpp4DNA甲基化，导致Dpp4表达减弱，从而降低血浆DPP4活性。我们的结论是，在青少年和成人状态下限制蛋白质是减少DPP4的充分策略，DPP4反过来有助于改善葡萄糖稳态。
Dipeptidyl peptidase 4 (DPP4) is known to be elevated in metabolic disturbances such as obesity, type 2 diabetes and fatty liver disease. Lowering DPP4 concentration by pharmacological inhibition improves glucose homeostasis and exhibits beneficial effects to reduce hepatic fat content. As factors regulating the endogenous expression ofDpp4are unknown, the aim of this study was to examine whether theDpp4expression is epigenetically regulated in response to dietary components. Primary hepatocytes were treated with different macronutrients, andDpp4mRNA levels and DPP4 activity were evaluated. Moreover, dietary low-protein intervention was conducted in New Zealand obese (NZO) mice, and subsequently, effects onDpp4expression, methylation as well as plasma concentration and activity were determined. Our results indicate thatDpp4mRNA expression is mediated by DNA methylation in several tissues. We therefore consider theDpp4southern shore as tissue differentially methylated region. Amino acids increasedDpp4expression in primary hepatocytes, whereas glucose and fatty acids were without effect. Dietary protein restriction in NZO mice increasedDpp4DNA methylation in liver leading to diminishedDpp4expression and consequently to lowered plasma DPP4 activity. We conclude that protein restriction in the adolescent and adult states is a sufficient strategy to reduce DPP4 which in turn contributes to improve glucose homeostasis.