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Hepatic Fat Accumulation Regulates Carnitine Palmitoyltransferase 1 (Cpt1a) Expression through Coordinated Epigenetic Mechanisms
Author(s) -
Moody Laura,
Jung Paul Mark,
Kriska Adam,
Chen Hong,
Pan YuanXiang
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.625.1
Subject(s) - biology , carnitine , epigenetics , regulation of gene expression , dna methylation , gene expression , beta oxidation , downregulation and upregulation , transcription factor , endocrinology , microbiology and biotechnology , biochemistry , metabolism , gene
Carnitine palmitoyltransferase 1 (Cpt1a) is a rate‐limiting enzyme that mediates the transport of fatty acids into the mitochondria for subsequent beta oxidation. Cpt1a is highly regulated at the transcriptional, translational, and substrate level. Epigenetic mechanisms regulating Cpt1a expression were investigated in the liver of rats fed a high fat diet. Hepatic Cpt1a mRNA was increased in response to high fat. High fat diet reduced DNA methylation and increased histone 3 lysine residue 4 dimethylation (H3K4Me2) both upstream of and within the promoter region of Cpt1a. This was accompanied by increased binding of C/EBPβ directly downstream of the Cpt1a transcription start site within the first intron. In addition to the transcriptional regulation of Cpt1a, expression of miR‐499, a predicted repressor of both Cpt1a and C/EBPβ, was also reduced. Treatment of rat hepatoma H4IIEC3 cells with non‐esterified fatty acid (NEFA) confirmed the correlation between the upregulation of Cpt1a gene expression and cellular fat accumulation. While H4IIEC3 cells transfected with non‐specific microRNA upregulated Cpt1a expression at high NEFA concentrations, exogenous overexpression of miR‐499 cells abolished this increase, resulting in suppressed beta oxidation and elevated lipid accumulation. We conclude that hepatic fat increases Cpt1a expression through a highly coordinated epigenetic mechanism including histone tail modifications and reduction of DNA methylation at specific chromatin locations, C/EBPβ transcription factor recruitment, as well as post‐transcriptional regulation by miR‐499. The spatial and temporal coordination of these epigenetic events at the Cpt1a locus will be further investigated to characterize gene regulation in fat metabolism.