Epigenetic regulation of carnitine palmitoyltransferase 1 (Cpt1a) by high fat diet

Laura Moody, Guanying Bianca Xu, Hong Chen, Yuan-Xiang Pan

Research output: Contribution to journalArticle

Abstract

Carnitine palmitoyltransferase 1 (Cpt1a) is a rate-limiting enzyme that mediates the transport of fatty acids into the mitochondria for subsequent beta-oxidation. The objective of this study was to uncover how diet mediates the transcriptional regulation of Cpt1a. Pregnant Sprague Dawley rats were exposed to either a high-fat (HF) or low-fat control diet during gestation and lactation. At weaning, male offspring received either a HF or control diet, creating 4 groups: lifelong control diet (C/C; n = 12), perinatal HF diet (HF/C; n = 9), post-weaning HF diet (C/HF; n = 10), and lifelong HF diet (HF/HF; n = 10). Only HF/HF animals had higher hepatic Cpt1a mRNA expression than C/C. Epigenetic analysis revealed reduced DNA methylation (DNAMe) and increased histone 3 lysine 4 dimethylation (H3K4Me2) upstream and within the promoter of Cpt1a in the HF/HF group. This was accompanied by increased peroxisome proliferator activated receptor alpha (PPARα) and CCAAT/enhancer binding protein beta (C/EBPβ) binding directly downstream of the Cpt1a transcription start site within the first intron. Findings were confirmed in rat hepatoma H4IIEC3 cells treated with non-esterified fatty acid (NEFA). After 12 h of NEFA treatment, there was an enrichment of SWI/SNF related matrix associated actin dependent regulator of chromatin subfamily D member 1 (BAF60a or SMARCD1) in the first intron of Cpt1a. We conclude that dietary fat elevates hepatic Cpt1a expression via a highly coordinated transcriptional mechanism involving increased H3K4Me2, reduced DNAMe, and recruitment of C/EBPβ PPARα PGC1α and BAF60a to the gene.

Original languageEnglish (US)
Pages (from-to)141-152
Number of pages12
JournalBiochimica et Biophysica Acta - Gene Regulatory Mechanisms
Volume1862
Issue number2
DOIs
StatePublished - Feb 2019

Fingerprint

Carnitine O-Palmitoyltransferase
High Fat Diet
Nutrition
Epigenomics
Fats
CCAAT-Enhancer-Binding Protein-beta
PPAR alpha
Fatty Acids
DNA Methylation
Diet
Weaning
Introns
Rats
Fat-Restricted Diet
Transcription Initiation Site
Dietary Fats
Liver
Lactation
Protein Binding
Histones

ASJC Scopus subject areas

  • Biophysics
  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Epigenetic regulation of carnitine palmitoyltransferase 1 (Cpt1a) by high fat diet. / Moody, Laura; Xu, Guanying Bianca; Chen, Hong; Pan, Yuan-Xiang.

In: Biochimica et Biophysica Acta - Gene Regulatory Mechanisms, Vol. 1862, No. 2, 02.2019, p. 141-152.

Research output: Contribution to journalArticle

@article{e0db05fd9ab541c8917ddee1befaa2f2,
title = "Epigenetic regulation of carnitine palmitoyltransferase 1 (Cpt1a) by high fat diet",
abstract = "Carnitine palmitoyltransferase 1 (Cpt1a) is a rate-limiting enzyme that mediates the transport of fatty acids into the mitochondria for subsequent beta-oxidation. The objective of this study was to uncover how diet mediates the transcriptional regulation of Cpt1a. Pregnant Sprague Dawley rats were exposed to either a high-fat (HF) or low-fat control diet during gestation and lactation. At weaning, male offspring received either a HF or control diet, creating 4 groups: lifelong control diet (C/C; n = 12), perinatal HF diet (HF/C; n = 9), post-weaning HF diet (C/HF; n = 10), and lifelong HF diet (HF/HF; n = 10). Only HF/HF animals had higher hepatic Cpt1a mRNA expression than C/C. Epigenetic analysis revealed reduced DNA methylation (DNAMe) and increased histone 3 lysine 4 dimethylation (H3K4Me2) upstream and within the promoter of Cpt1a in the HF/HF group. This was accompanied by increased peroxisome proliferator activated receptor alpha (PPARα) and CCAAT/enhancer binding protein beta (C/EBPβ) binding directly downstream of the Cpt1a transcription start site within the first intron. Findings were confirmed in rat hepatoma H4IIEC3 cells treated with non-esterified fatty acid (NEFA). After 12 h of NEFA treatment, there was an enrichment of SWI/SNF related matrix associated actin dependent regulator of chromatin subfamily D member 1 (BAF60a or SMARCD1) in the first intron of Cpt1a. We conclude that dietary fat elevates hepatic Cpt1a expression via a highly coordinated transcriptional mechanism involving increased H3K4Me2, reduced DNAMe, and recruitment of C/EBPβ PPARα PGC1α and BAF60a to the gene.",
author = "Laura Moody and Xu, {Guanying Bianca} and Hong Chen and Yuan-Xiang Pan",
year = "2019",
month = "2",
doi = "10.1016/j.bbagrm.2018.12.009",
language = "English (US)",
volume = "1862",
pages = "141--152",
journal = "Biochimica et Biophysica Acta - Gene Regulatory Mechanisms",
issn = "1874-9399",
publisher = "Elsevier",
number = "2",

}

TY - JOUR

T1 - Epigenetic regulation of carnitine palmitoyltransferase 1 (Cpt1a) by high fat diet

AU - Moody, Laura

AU - Xu, Guanying Bianca

AU - Chen, Hong

AU - Pan, Yuan-Xiang

PY - 2019/2

Y1 - 2019/2

N2 - Carnitine palmitoyltransferase 1 (Cpt1a) is a rate-limiting enzyme that mediates the transport of fatty acids into the mitochondria for subsequent beta-oxidation. The objective of this study was to uncover how diet mediates the transcriptional regulation of Cpt1a. Pregnant Sprague Dawley rats were exposed to either a high-fat (HF) or low-fat control diet during gestation and lactation. At weaning, male offspring received either a HF or control diet, creating 4 groups: lifelong control diet (C/C; n = 12), perinatal HF diet (HF/C; n = 9), post-weaning HF diet (C/HF; n = 10), and lifelong HF diet (HF/HF; n = 10). Only HF/HF animals had higher hepatic Cpt1a mRNA expression than C/C. Epigenetic analysis revealed reduced DNA methylation (DNAMe) and increased histone 3 lysine 4 dimethylation (H3K4Me2) upstream and within the promoter of Cpt1a in the HF/HF group. This was accompanied by increased peroxisome proliferator activated receptor alpha (PPARα) and CCAAT/enhancer binding protein beta (C/EBPβ) binding directly downstream of the Cpt1a transcription start site within the first intron. Findings were confirmed in rat hepatoma H4IIEC3 cells treated with non-esterified fatty acid (NEFA). After 12 h of NEFA treatment, there was an enrichment of SWI/SNF related matrix associated actin dependent regulator of chromatin subfamily D member 1 (BAF60a or SMARCD1) in the first intron of Cpt1a. We conclude that dietary fat elevates hepatic Cpt1a expression via a highly coordinated transcriptional mechanism involving increased H3K4Me2, reduced DNAMe, and recruitment of C/EBPβ PPARα PGC1α and BAF60a to the gene.

AB - Carnitine palmitoyltransferase 1 (Cpt1a) is a rate-limiting enzyme that mediates the transport of fatty acids into the mitochondria for subsequent beta-oxidation. The objective of this study was to uncover how diet mediates the transcriptional regulation of Cpt1a. Pregnant Sprague Dawley rats were exposed to either a high-fat (HF) or low-fat control diet during gestation and lactation. At weaning, male offspring received either a HF or control diet, creating 4 groups: lifelong control diet (C/C; n = 12), perinatal HF diet (HF/C; n = 9), post-weaning HF diet (C/HF; n = 10), and lifelong HF diet (HF/HF; n = 10). Only HF/HF animals had higher hepatic Cpt1a mRNA expression than C/C. Epigenetic analysis revealed reduced DNA methylation (DNAMe) and increased histone 3 lysine 4 dimethylation (H3K4Me2) upstream and within the promoter of Cpt1a in the HF/HF group. This was accompanied by increased peroxisome proliferator activated receptor alpha (PPARα) and CCAAT/enhancer binding protein beta (C/EBPβ) binding directly downstream of the Cpt1a transcription start site within the first intron. Findings were confirmed in rat hepatoma H4IIEC3 cells treated with non-esterified fatty acid (NEFA). After 12 h of NEFA treatment, there was an enrichment of SWI/SNF related matrix associated actin dependent regulator of chromatin subfamily D member 1 (BAF60a or SMARCD1) in the first intron of Cpt1a. We conclude that dietary fat elevates hepatic Cpt1a expression via a highly coordinated transcriptional mechanism involving increased H3K4Me2, reduced DNAMe, and recruitment of C/EBPβ PPARα PGC1α and BAF60a to the gene.

UR - http://www.scopus.com/inward/record.url?scp=85060225802&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85060225802&partnerID=8YFLogxK

U2 - 10.1016/j.bbagrm.2018.12.009

DO - 10.1016/j.bbagrm.2018.12.009

M3 - Article

C2 - 30605728

AN - SCOPUS:85060225802

VL - 1862

SP - 141

EP - 152

JO - Biochimica et Biophysica Acta - Gene Regulatory Mechanisms

JF - Biochimica et Biophysica Acta - Gene Regulatory Mechanisms

SN - 1874-9399

IS - 2

ER -