The epigenetic regulation of paraoxonase 1 (PON1) as an important enzyme in HDL function: The missing link between environmental and genetic regulation

Background: Paraoxonase 1 (PON1) is an important antiatherogenic and antioxidant enzyme in the circulation that has been associated with adverse health outcomes particularly cardiovascular disease (CVD) and other metabolic disorders. PON1 is a highly promiscuous enzyme and can hydrolyse a large variety of substrates, however, detailed structure/function studies have concluded that the natural substrates for PON1 are lipophilic lactones. The interindividual variability in PON1 activity has been mainly attributed to genetic determinants; however, it appears that the contribution of epigenetics has been ignored as a result of the lack of adequate research. Content: Epigenetic processes, including the histone modifications in the PON1 gene, the methylation of CpG sites in the promoter region of the PON1 gene and the microRNA modulation of PON1 expression can be responsible for the under researched gap between the environmental and genetic regulation of PON1. Environmental factors, including diet, pollution and lifestyle-related factors widely differ between individuals and populations and can cause large differences in the distribution of PON1 and it is important to note that their effects may be exerted through the epigenetic processes. This review discusses and emphasizes the importance of the epigenetic regulation of PON1 as a less-studied subject to highlight future research landscapes. Summary: Epigenetic regulation is known as an important contributor to the pathogenesis of human diseases, particularly multifactorial diseases such as CVD, which is life-threatening. Due to the importance of PON1 in the functionality of high-density lipoprotein (HDL) and its association with CVD, further explorations of its epigenetic regulation using advanced methods such as Methyl-Seq may lead to the identification of new epigenetic contributors that in turn may lead to targeted therapies.