NAFLD is a common multi-factorial disease characterized by increased hepatic fat. Although NAFLD associates with increased risk of atherosclerotic cardiovascular disease, we speculate that this risk could differ in the different NAFLD subtypes, e.g. metabolically or genetically-driven. Recently, by comparing subjects with NAFLD due to metabolic disturbances to those with genetic NAFLD due to rs738409 PNPLA3 MM genotype, we found that the burden of carotid intima-media thickness was higher in metabolically but not in genetically-driven NAFLD. A mechanistic explanation of this difference is not available.
Previous studies indicated that the ability of HDL to mediate the cholesterol inflow and outflow from macrophages, otherwise defined as cholesterol efflux (CEC) and cholesterol loading capacity (CLC), play an important role in atherogenesis. Therefore, the evaluation of HDL function might shed lights on the pathophysiological mechanisms relating NAFLD subtypes to the risk of atherosclerosis. Unfortunately, scanty data are available on HDL functionality in NAFLD. Our experimental hypothesis is that HDL may be dysfunctional in metabolically, but not in genetically-driven NFLD, thus explaining the difference in C-IMT values we have seen between these two conditions.
To test this hypothesis we plan to evaluate if there are any differences in the ex vivo values of CEC and CLC in three groups: 1) 10 subjects with at least 3 factors of MetS, PNPLA3 wild-type genotype and MRS-defined NAFLD (Metabolic group 1), 2) 10 blood donors carrying M148M PNPLA3 genotype with MRS-defined NAFLD (Genetic group) and 3) 10 healthy blood donors, PNPLA3 wild-types and without MRS-defined NAFLD (Controls). Changes of HDL composition between the groups will be also evaluated.
The identification of differences in the cholesterol reverse transport between NAFLD subtypes might have a potential relevance in the development of future pharmacological strategies to prevent atherosclerosis.
