Faculty Collaboration Database

A maternal high-fat diet modulates fetal SIRT1 histone and protein deacetylase activity in nonhuman primates. FASEB J 2012 Dec;26(12):5106-14

Date

09/18/2012

Pubmed ID

22982377

Pubmed Central ID

PMC3509051

DOI

10.1096/fj.12-212878

Scopus ID

2-s2.0-84870316797 (requires institutional sign-in at Scopus site)   154 Citations

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.

Author List

Suter MA, Chen A, Burdine MS, Choudhury M, Harris RA, Lane RH, Friedman JE, Grove KL, Tackett AJ, Aagaard KM

MESH terms used to index this publication - Major topics in bold

Acetylation
Animals
Blotting, Western
COS Cells
Catalytic Domain
Diet, High-Fat
Female
Fetus
Gene Expression Regulation, Developmental
Histone Deacetylases
Histones
Liver
Lysine
Macaca
Male
Mass Spectrometry
Mutation
Pregnancy
Reverse Transcriptase Polymerase Chain Reaction
Sirtuin 1
Substrate Specificity
p300-CBP Transcription Factors