Paternal hyperglycemia induces transgenerational inheritance of susceptibility to hepatic steatosis in rats involving altered methylation on Ppara promoter

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1865

Article

Li, Xinyu^1,2,3,4  Shi, Xiaoqin^1,2  Hou, Yi^1,2  Cao, Xuemei^1,2  Gong, Lei^1,2  Wang, Hongying^1,2  Li, Jiayu^1,2  Li, Jibin⁴  Wu, Chaodong⁶  Xiao, Daliao⁷  Qi, Hongbo¹  Xiao, Xiaoqiu^1,2,5 

[1] Chongqing Med Univ, Affiliated Hosp 1, Dept Obstet & Gynecol, Chongqing 400016, Peoples R China

[2] Chongqing Med Univ, Affiliated Hosp 1, Chongqing Key Lab Translat Med Major Metab Dis, Chongqing 400016, Peoples R China

[3] Chongqing Med Univ, Affiliated Hosp 1, Dept Pharm, Chongqing 400016, Peoples R China

[4] Chongqing Med Univ, Sch Publ Hlth & Management, Dept Nutr & Food Hyg, Chongqing 400016, Peoples R China

[5] Chongqing Med Univ, Canada China New Zealand Joint Lab Maternal & Fet, Chongqing 400016, Peoples R China

[6] Texas A&M Univ, Dept Nutr & Food Sci, College Stn, TX 77843 USA

[7] Loma Linda Univ, Sch Med, Dept Basic Sci, Ctr Perinatal Biol, Loma Linda, CA 92354 USA

关键词: Epigenetics;    Paternal hyperglycemia;    Lipid metabolism;    Methylation;    Hepatic steatosis;    Transgenerational inheritance;   

DOI  :  10.1016/j.bbadis.2018.10.040

来源: Elsevier

【 摘 要 】

Objective: Diabetes 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 inter generational effect in mammals as well as the underlying mechanisms. Methods: Hyperglycemia 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. Results: Paternal 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-1 alpha, 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. Conclusions: Paternal 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.

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