Epigenetics of Lipid Phenotypes

Abstract

Dyslipidemia is a well-established risk factor for cardiovascular disease, the main cause of death worldwide. Blood lipid profiles are patterned by both genetic and environmental factors. In recent years, epigenetics has emerged as a paradigm that unifies these influences. In this review, we have summarized the latest evidence implicating epigenetic mechanisms—DNA methylation, histone modification, and regulation by RNAs—in lipid homeostasis. Key findings have emerged in a number of novel epigenetic loci located in biologically plausible genes (e.g. CPT1A, ABCG1, SREBF1, and others), as well as microRNA-33a/b. Evidence from animal and cell culture models suggests a complex interplay between different classes of epigenetic processes in the lipid-related genomic regions. While epigenetic findings hold the potential to explain the interindividual variability in lipid profiles as well as the underlying mechanisms, they have yet to be translated into effective therapies for dyslipidemia.

Maternal obesity alters fatty acid oxidation, AMPK activity, and associated DNA methylation in mesenchymal stem cells from human infants

“…Therefore, our sample size is relatively small in comparison to epigenome-wide association studies (EWAS), but warranted for completing the in-depth metabolic phenotyping of the MSCs that is not feasible in archived tissue or blood samples. Nevertheless, our results are consistent with adult EWAS investigations, where two CpGs we identified in the CPT1A DMR (cg00574958 and cg17058475) were associated with blood lipid profiles in humans [45] , [46] . Some groups have associated differential methylation of these CpGs with intrauterine famine exposure [32] , [33] , strengthening the hypothesis that intrauterine metabolic disturbances introduce stable epigenetic modifications in fetal cells and tissues that we are able to detect in human umbilical cord-derived MSCs.…”

DNA methylation in human lipid metabolism and related diseases

“…Furthermore, other epigenetic layers need to gain importance, for example, the interplay between microRNAs and other epigenetic regulators such as histone modifications and DNA methylation. For example, it is becoming increasingly evident that post-transcriptional repression by microRNAs, a class of small noncoding RNAs, is a key layer of regulation in several biological processes, including lipid phenotypes [ 60 ]. The NIH Roadmap Epigenomics Consortium has generated a large collection of human epigenomes for primary cells and tissues, describing the integrative analysis of 111 reference human epigenomes generated as part of the program, profiled for histone modification patterns, DNA accessibility, DNA methylation, and RNA expression, providing a unique resource for such investigations [ 61 ].…”

Excessive early-life cholesterol exposure may have later-life consequences for nonalcoholic fatty liver disease

“…97 Epigenetic mechanism of MHC Epigenetics refers to heritable changes in gene expression and translation that do not involve modifications in the underlying DNA sequence 98 that influence metabolism and phenotype. 99 Further, epigenetic modifications have been implicated as key modulators in the malprogramming of offspring metabolic health. 100,101 DNA methylation, the most extensively studied epigenetic mechanism, silences gene transcription through the methylation of CpG-rich islands in the promoter or enhancer regions of the gene of interest.…”