Paternal hyperglycemia induces transgenerational inheritance of susceptibility to hepatic steatosis in rats involving altered methylation on Ppara promoter
Paternal hyperglycemia induces transgenerational inheritance of susceptibility to hepatic steatosis in rats involving altered methylation on Ppara promoter
复制标题
父亲高血糖诱导大鼠肝脂肪变性易感性的跨代遗传，涉及 Ppara 启动子甲基化的改变
DOI：
10.1016/j.bbadis.2018.10.040
复制
发表时间：
2019-01-01
影响因子：
6.2
通讯作者：
Xiao，Xiaoqiu
中科院分区：
文献类型：
--
作者：
Li，Xinyu;Shi，Xiaoqin;Xiao，Xiaoqiu
ObjectiveDiabetes exerts adverse effects on the initiation or progression of diabetes and metabolic syndrome in the next generation. In past studies, limited attention has been given to the fathers' role in shaping the metabolic landscape of offspring. Our study was designed to investigate how paternal hyperglycemia exerts an intergenerational effect in mammals as well as the underlying mechanisms.MethodsHyperglycemia was introduced in male rats by intraperitoneally injected streptozotocin and these males were bred with healthy females to generate offspring. The metabolic profiles of the progeny were assessed; DNA methylation profiles and gene expression were investigated. Mutagenesis constructs of the Ppara promoter region, and a luciferase reporter assay were used to determine transcription factor binding sites (TFBSs) and the effects of hypermethylation on Ppara transcription.ResultsPaternal hyperglycemia induced increased liver weight, and plasma TC, TG, LDL, accumulation of triglycerides in the liver. We discovered that CpG 13 in the amplified promoter region (−852 to −601) of Ppara was hypermethylated in adult offspring liver and expression of Ppara, Acox1, Cpt-1α, and Cd36 was down regulated. Hypermethylation of CpG site 13 in the Ppara promoter inhibited the gene transcription, probably through abrogation of SP1 binding. The same epigenetic alteration was discovered in the fetus (E16.5) liver of hyperglycemic father's progeny.ConclusionsPaternal hyperglycemia may induce epigenetic modification of Ppara in offspring's liver, probably through interaction with SP1 binding, causing impaired lipid metabolism. Our investigation may have implications for the understanding of father-offspring interactions with the potential to account for metabolic syndromes.
