A maternal high-fat diet modulates fetal SIRT1 histone and protein deacetylase activity in nonhuman primates
| Autor: | Aishe Chen, Kjersti Aagaard, R. Alan Harris, Kevin L. Grove, Robert H. Lane, Marie Schluterman Burdine, Jacob E. Friedman, Mahua Choudhury, Melissa J. Suter, Alan J. Tackett |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Male
medicine.medical_specialty Blotting Western P300-CBP Transcription Factors Diet High-Fat Biochemistry Histone Deacetylases Mass Spectrometry Research Communications Substrate Specificity Histones Histone H3 Fetus Sirtuin 1 Pregnancy Internal medicine Catalytic Domain Genetics medicine Animals p300-CBP Transcription Factors Molecular Biology Epigenomics biology Protein deacetylase activity Reverse Transcriptase Polymerase Chain Reaction Lysine Gene Expression Regulation Developmental Acetylation Molecular biology Endocrinology Liver COS Cells Mutation biology.protein Macaca Female Histone deacetylase activity Biotechnology Deacetylase activity |
| Popis: | 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.—Suter, M. A., Chen, A., Burdine, M. S., Choudhury, M., Harris, R. A., Lane, R. H., Friedman, J. E., Grove, K. L., Tackett, A. J., Aagaard, K. M. A maternal high-fat diet modulates fetal SIRT1 histone and protein deacetylase activity in nonhuman primates. |
| Databáze: | OpenAIRE |
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