title: A maternal high-fat diet modulates fetal SIRT1 histone and protein deacetylase activity in nonhuman primates.
abstract: In nonhuman primates, we previously demonstrated that a maternal high-fat diet (MHFD) induces fetal nonalcoholic fatty liver disease (NAFLD) and alters the fetal metabolome. These changes are accompanied by altered acetylation of histone H3 (H3K14ac). However, the mechanism behind this alteration in acetylation remains unknown. As SIRT1 is both a lysine deacetylase and a crucial sensor of cellular metabolism, we hypothesized that SIRT1 may be involved in fetal epigenomic alterations. Here we show that in utero exposure to a MHFD, but not maternal obesity per se, increases fetal H3K14ac with concomitant decreased SIRT1 expression and diminished in vitro protein and histone deacetylase activity. MHFD increased H3K14ac and DBC1-SIRT1 complex formation in fetal livers, both of which were abrogated with diet reversal despite persistent maternal obesity. Moreover, MHFD was associated with altered expression of known downstream effectors deregulated in NAFLD and modulated by SIRT1 (e.g., PPARΑ, PPARG, SREBF1, CYP7A1, FASN, and SCD). Finally, ex vivo purified SIRT1 retains deacetylase activity on an H3K14ac peptide substrate with preferential activity toward acetylated histone H3; mutagenesis of the catalytic domain of SIRT1 (H363Y) abrogates H3K14ac deacetylation. Our data implicate SIRT1 as a likely molecular mediator of the fetal epigenome and metabolome under MHFD conditions.
authors.affiliation: Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Suter
authors.forename: Aishe
authors.initials: A
authors.lastname: Chen
authors.forename: Marie S
authors.initials: MS
authors.lastname: Burdine
authors.forename: Mahua
authors.initials: M
authors.lastname: Choudhury
authors.forename: R Alan
authors.initials: RA
authors.lastname: Harris
authors.forename: Robert H
authors.initials: RH
authors.lastname: Lane
authors.forename: Jacob E
authors.initials: JE
authors.lastname: Friedman
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Grove
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Tackett
authors.forename: Kjersti M
authors.initials: KM
authors.lastname: Aagaard
mesh_terms: D000107:Acetylation; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D020134:Catalytic Domain / Q000235:genetics; D059305:Diet, High-Fat; D005260:Female; D005333:Fetus / Q000201:enzymology; D018507:Gene Expression Regulation, Developmental; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D008099:Liver / Q000196:embryology / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D008251:Macaca / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D009154:Mutation; D011247:Pregnancy; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D006657:Histones; D050880:p300-CBP Transcription Factors; D056564:Sirtuin 1; D006655:Histone Deacetylases; D008239:Lysine