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.
Our previous results have suggested an essential role of metabolic abnormalities in increasing the burden of subclinical atherosclerosis in NAFLD thus identifying two different subtypes of NAFLD disease associated with a different natural history and atherosclerosis progression. However, in this study we did not specifically studied any mechanistic pathway that could explain our observation. A robust inverse association between the level of HDL-C and the risk of cardiovascular disease has been reported. However, some findings have suggested a specific role of HDL function (instead concentration) in atheroprotection. The ability of HDL to promote cholesterol efflux from macrophages is strongly and inversely associated with both subclinical atherosclerosis and obstructive coronary artery disease even after adjustment for traditional cardiovascular risk factors, including the levels of HDL-C and apolipoprotein A-I [J Intern Med. 2008; 263(3):256-73]. Unfortunately, no information was provided on HDL functionality in Mets subjects that could contribute to the higher cardiovascular risk observed in patients with NAFLD.
Given all these data, we decided to test if there is impairment in CEC and CLC in metabolically vs. genetically determined NAFLD and if this could explain differences in subclinical atherosclerosis. This project could offer important acknowledgment in clinical practice. For example, evaluating the cardiovascular risk profile of patients with NAFLD disease, one could suppose that the crucial cause of CVD progression in these patients is enclosed in metabolic abnormalities and obesity and not in fatty liver accumulation per se. A healthy patient with fat accumulation in the liver, due to the presence of rs738409 I148M gene variant, could benefit from the genetic screening for PNPLA3 polymorphism to evaluate the risk of liver disease progression but not the cardiovascular risk stratification. The identification of potential disturbances in cholesterol reverse transport in NAFLD might have a potential relevance in the development of future pharmacological strategies.