title: Downregulation of miR-150 Expression by DNA Hypermethylation Is Associated with High 2-Hydroxy-(4-methylthio)butanoic Acid-Induced Hepatic Cholesterol Accumulation in Nursery Piglets.
abstract: Excess 2-hydroxy-(4-methylthio)butanoic acid (HMB) supplementation induces hyperhomocysteinemia, which contributes to hepatic cholesterol accumulation. However, it is unclear whether and how high levels of HMB break hepatic cholesterol homeostasis in nursery piglets. In this study, HMB oversupplementation suppressed food intake and decreased body weight in nursery piglets. Hyperhomocysteinemia and higher hepatic cholesterol accumulation were observed in HMB groups. Accordingly, HMB significantly increased the protein content of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) and glycine N-methyltransferase (GNMT) but decreased that of acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT1). Significant downregulation of miR-150, miR-181d-5p, and miR-296-3p targeting the 3'-untranslated regions (UTRs) of GNMT and HMGCR was detected in the liver of HMB-treated piglets, and their functional validation was confirmed by dual-luciferase reporter assay. Furthermore, hypermethylation of miR-150 promoter was detected in association with suppressed miR-150 expression in the livers of HMB-treated piglets. This study indicated a new mechanism of hepatic cholesterol unhomeostasis by dietary methyl donor supplementation.
authors.affiliation: Key Laboratory of Animal Physiology & Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University , Nanjing 210095, People's Republic of China.
authors.forename: Yimin
authors.initials: Y
authors.lastname: Jia
authors.affiliation: Key Laboratory of Animal Physiology & Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University , Nanjing 210095, People's Republic of China.
authors.forename: Mingfa
authors.initials: M
authors.lastname: Ling
authors.affiliation: Key Laboratory of Animal Physiology & Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University , Nanjing 210095, People's Republic of China.
authors.forename: Luchu
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Animal Physiology & Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University , Nanjing 210095, People's Republic of China.
authors.forename: Shuxia
authors.initials: S
authors.lastname: Jiang
authors.affiliation: China Feed Industry Association, Ministry of Agriculture , Peking 100125, People's Republic of China.
authors.forename: Yusheng
authors.initials: Y
authors.lastname: Sha
authors.affiliation: Key Laboratory of Animal Physiology & Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University , Nanjing 210095, People's Republic of China.|Jiangsu Collaborative Innovation Center of Meat Production and Processing, Quality and Safety Control, Nanjing Agricultural University , Nanjing 210095, People's Republic of China.
authors.forename: Ruqian
authors.initials: R
authors.lastname: Zhao
mesh_terms: D020413:3' Untranslated Regions; D000101:Acetyl-CoA C-Acetyltransferase / Q000235:genetics; D000821:Animal Feed; D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight / Q000187:drug effects; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D015536:Down-Regulation; D005786:Gene Expression Regulation / Q000187:drug effects; D050938:Glycine N-Methyltransferase / Q000235:genetics; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008715:Methionine / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D035683:MicroRNAs / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034421:Sus scrofa
chemical_list: D020413:3' Untranslated Regions; D035683:MicroRNAs; C008391:alpha-hydroxy-gamma-methylmercaptobutyric acid; D002784:Cholesterol; D008715:Methionine; D006903:Hydroxymethylglutaryl CoA Reductases; D050938:Glycine N-Methyltransferase; D000101:Acetyl-CoA C-Acetyltransferase
keywords: DNA methylation; HMB; cholesterol; microRNA; nursery piglets