Differential epigenetic and transcriptional response of the skeletal muscle carnitine palmitoyltransferase 1B (CPT1B) gene to lipid exposure with obesity.
Jill M MaplesJeffrey John BraultCarol A WitczakSanghee ParkMonica J HubalTodd M WeberJoseph A HoumardBrian M ShewchukPublished in: American journal of physiology. Endocrinology and metabolism (2015)
The ability to increase fatty acid oxidation (FAO) in response to dietary lipid is impaired in the skeletal muscle of obese individuals, which is associated with a failure to coordinately upregulate genes involved with FAO. While the molecular mechanisms contributing to this metabolic inflexibility are not evident, a possible candidate is carnitine palmitoyltransferase-1B (CPT1B), which is a rate-limiting step in FAO. The present study was undertaken to determine if the differential response of skeletal muscle CPT1B gene transcription to lipid between lean and severely obese subjects is linked to epigenetic modifications (DNA methylation and histone acetylation) that impact transcriptional activation. In primary human skeletal muscle cultures the expression of CPT1B was blunted in severely obese women compared with their lean counterparts in response to lipid, which was accompanied by changes in CpG methylation, H3/H4 histone acetylation, and peroxisome proliferator-activated receptor-δ and hepatocyte nuclear factor 4α transcription factor occupancy at the CPT1B promoter. Methylation of specific CpG sites in the CPT1B promoter that correlated with CPT1B transcript level blocked the binding of the transcription factor upstream stimulatory factor, suggesting a potential causal mechanism. These findings indicate that epigenetic modifications may play important roles in the regulation of CPT1B in response to a physiologically relevant lipid mixture in human skeletal muscle, a major site of fatty acid catabolism, and that differential DNA methylation may underlie the depressed expression of CPT1B in response to lipid, contributing to the metabolic inflexibility associated with severe obesity.
Keyphrases
- dna methylation
- skeletal muscle
- fatty acid
- genome wide
- insulin resistance
- transcription factor
- gene expression
- weight loss
- metabolic syndrome
- copy number
- adipose tissue
- type diabetes
- nuclear factor
- poor prognosis
- polycystic ovary syndrome
- dna binding
- binding protein
- body mass index
- high fat diet induced
- toll like receptor
- genome wide identification
- immune response
- weight gain
- induced pluripotent stem cells
- hydrogen peroxide
- risk assessment
- human health
- bone mineral density
- histone deacetylase
- heat stress
- long non coding rna