title: Maternal dietary betaine supplementation modifies hepatic expression of cholesterol metabolic genes via epigenetic mechanisms in newborn piglets.
abstract: To elucidate the effects of maternal dietary betaine supplementation on hepatic expression of cholesterol metabolic genes in newborn piglets and the involved epigenetic mechanisms, we fed gestational sows with control or betaine-supplemented diets (3 g/kg) throughout pregnancy. Neonatal piglets born to betaine-supplemented sows had higher serum methionine concentration and hepatic content of betaine, which was associated with significantly up-regulated hepatic expression of glycine N-methyltransferase. Prenatal betaine exposure increased hepatic cholesterol content and modified the hepatic expression of cholesterol metabolic genes in neonatal piglets. Sterol regulatory element-binding protein 2 was down-regulated at both mRNA and protein levels, while 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR) was down-regulated at the mRNA level, but up-regulated at the protein level, in betaine-exposed piglets. The transcriptional repression of HMGCR was associated with CpG island hypermethylation and higher repressive histone mark H3K27me3 (histone H3 lysine 27 trimethylation) on the promoter, whereas increased HMGCR protein content was associated with significantly decreased expression of miR-497. Furthermore, LDL receptor was significantly down-regulated at both mRNA and protein levels in the liver of betaine-exposed piglets, which was associated with promoter CpG hypermethylation. In addition, the expression of cholesterol-27α-hydroxylase (CYP27α1) was up-regulated at both mRNA and protein levels, while the expression of cholesterol-7α-hydroxylase (CYP7α1) was increased at the mRNA level, but unchanged at the protein level associated with increased expression of miR-181. These results indicate that maternal betaine supplementation increases hepatic cholesterol content in neonatal piglets through epigenetic regulations of cholesterol metabolic genes, which involve alterations in DNA and histone methylation and in the expression of microRNA targeting these genes.
authors.affiliation: Key Laboratory of Animal Physiology and Biochemistry, Nanjing Agricultural University,Nanjing210095,People's Republic of China.
authors.forename: Demin
authors.initials: D
authors.lastname: Cai
authors.affiliation: Key Laboratory of Animal Physiology and Biochemistry, Nanjing Agricultural University,Nanjing210095,People's Republic of China.
authors.forename: Yimin
authors.initials: Y
authors.lastname: Jia
authors.affiliation: Key Laboratory of Animal Physiology and Biochemistry, Nanjing Agricultural University,Nanjing210095,People's Republic of China.
authors.forename: Jingyu
authors.initials: J
authors.lastname: Lu
authors.affiliation: Key Laboratory of Animal Physiology and Biochemistry, Nanjing Agricultural University,Nanjing210095,People's Republic of China.
authors.forename: Mengjie
authors.initials: M
authors.lastname: Yuan
authors.affiliation: Key Laboratory of Animal Physiology and Biochemistry, Nanjing Agricultural University,Nanjing210095,People's Republic of China.
authors.forename: Shiyan
authors.initials: S
authors.lastname: Sui
authors.affiliation: Key Laboratory of Animal Physiology and Biochemistry, Nanjing Agricultural University,Nanjing210095,People's Republic of China.
authors.forename: Haogang
authors.initials: H
authors.lastname: Song
authors.affiliation: Key Laboratory of Animal Physiology and Biochemistry, Nanjing Agricultural University,Nanjing210095,People's Republic of China.
authors.forename: Ruqian
authors.initials: R
authors.lastname: Zhao
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001622:Betaine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001647:Bile Acids and Salts / Q000097:blood; D002784:Cholesterol / Q000032:analysis / Q000097:blood / Q000235:genetics*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics; D019175:DNA Methylation; D004032:Diet / Q000662:veterinary; D019587:Dietary Supplements; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics; D008099:Liver / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D039382:Maternal Nutritional Physiological Phenomena; D008715:Methionine / Q000097:blood / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics; D011247:Pregnancy; D012333:RNA, Messenger / Q000032:analysis; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics; D034421:Sus scrofa
chemical_list: D001647:Bile Acids and Salts; D035683:MicroRNAs; D012333:RNA, Messenger; D051782:Sterol Regulatory Element Binding Protein 2; D001622:Betaine; D002784:Cholesterol; D008715:Methionine; D006903:Hydroxymethylglutaryl CoA Reductases; D002790:Cholesterol 7-alpha-Hydroxylase