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

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 (PPAR alpha) and CCAAT/enhancer binding protein beta (C/EBP beta) 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/EBP beta, PPAR alpha, PGC1 alpha, and BAF60a to the gene.