Fig. 7

Molecular mechanism proposed for PON1 in NAFLD pathophysiology. Schematic representation of the suggested gene-regulatory effect of rs705379:C > T on NAFLD pathogenesis. The PON1 polymorphism is located in the promoter region of PON1 and identified to bind transcription factor Specific protein 1 (Sp1) in an interactive manner with sterol regulatory element-binding protein-2 (SREBP-2). Sp1 is known to initiate PON1 transcription in a methylation-dependent manner while SREBP-2 is implicated in cholesterol homeostasis. Two different scenarios are possible depending on which polymorphic variant is present. a SNP rs705379:C results in hypomethylation-induced expression and activity of PON1. Simultaneously, SREBP-2 upregulation is observed resulting in hepatic cholesterol accumulation and increased susceptibility for NAFLD/NASH development. b SNP rs705379:T alters transcription factor binding affinity thereby resulting in hypermethylation-induced silencing, normal SREBP-2 levels and correct functioning of the liver. Figure was created with BioRender.com