Methylation in CPT1A, lipoproteins, and epigenetics

Chapter

Abstract

  • Abnormal concentrations of lipoproteins in the plasma have long been known to associate with morbidity and mortality due to their role in promoting atherosclerosis. Lipoprotein homeostasis is influenced, in part, by heritable factors; however, known lipid-associated single-nucleotide polymorphisms account for a modest proportion of phenotypic variability. CPT1A encodes the hepatic isoform of carnitine palmitoyltransferase 1 (CPT1), a key enzyme in fatty acid metabolism, and presents an interesting object of study in this context. Candidate gene and genome-wide association studies have failed to generate compelling evidence for the role of CPT1A mutations in complex disease in the general population, although functional mutation present in the Arctic have been shown to be cardioprotective. The methylation of intronic loci in CPT1A, on the other hand, has been recently robustly linked to lipid traits, with the associations replicated in a variety of populations. The underlying mechanisms remain to be elucidated, but evidence has emerged that microRNAs 33a and 33b (located within transcription factors SREBF2 and SREBF1, respectively) repress several genes involved in fatty acid oxidation (including CPT1A) and cholesterol transport (including ABCA1 and ABCG1). It is uncertain whether CPT1A methylation causes dyslipidemia or whether dyslipidemia causes CPT1A methylation, and because DNA methylation at CPT1A loci is largely independent of sequence variation, Mendelian randomization analysis provides little insight. Translating the findings of epigenetic studies of CPT1A and dyslipidemias into clinical applications is complicated by a number of factors, including the fact that most human research has made use of proxy tissues (derived from blood, not adipose or liver) and little research has placed epigenomic findings in the context of other -omics (e.g., variation of the gut microbiome).
  • Digital Object Identifier (doi)

    International Standard Book Number (isbn) 13

  • 9783319555294
  • Start Page

  • 387
  • End Page

  • 403
  • Volume

  • 1