Non-Alcoholic Fatty Liver Disease (NAFLD) is a common multi-factorial disease characterized by increased hepatic fat. Although NAFLD associates with the risk of atherosclerotic cardiovascular disease (ASCVD), this risk could differ in the different NAFLD subtypes, e.g. metabolically or genetically driven.
The I148M PNPLA3 variant accounts for the largest fraction of genetic predisposition to NAFLD independent from metabolic risk factors. Recently, comparing subjects with Metabolic NAFLD due to metabolic disturbances to those with Genetic NAFLD due to PNPLA3 MM genotype, we found that excess hepatic fat (HF) increases the burden of subclinical atherosclerosis, as estimated by carotid intima-media thickness, only in Metabolic NAFLD.
It is well known that postprandial lipemia is an important cardiometabolic risk factor superior to fasting lipid levels in predicting atherosclerosis risk. Several lines of evidences have shown a close correlation between liver fat content and postprandial lipid disturbances. Moreover, NAFLD patients developing ASCVD have increased concentration of remnants, a lipoprotein class mainly generated during the post-prandial period. Therefore, we have hypothesized that the increased risk of vascular damage associated to Metabolic NAFLD may be related to a delay in the lipid and lipoprotein metabolism during the post-prandial phase as compared to Genetic NAFLD.
Few studies have investigated the postprandial metabolism of lipoproteins in NAFLD and none have separately considered metabolically vs. genetically driven NAFLD. Thus, we aim to investigate if there are any differences in the dynamic response of lipoprotein metabolism after an oral high fat meal in: 1) 15 subjects with, PNPLA3 wild-type genotype, MRS-defined NAFLD and metabolic syndrome (Metabolic group), 2) 10 blood donors carrying M148M PNPLA3 genotype with MRS-defined NAFLD (Genetic group) and 3) 20 blood donors, PNPLA3 wild-types and without MRS-defined NAFLD (Controls).
In our previous studies, we have tried to clarify whether fatty liver itself promotes vascular damage. We have compared subclinical atherosclerosis between two human models of NAFLD disease due to completely different causative mechanisms. In our previous experiment, subjects with Metabolic NAFLD had higher C-IMT and exhibited the full spectrum of metabolic syndrome (MetS), such as visceral obesity, atherogenic dyslipidaemia (higher triglycerides and lower HDL-C) and insulin resistance as compared with other groups (all p
Increasing evidence indicates that impaired metabolism of postprandial lipoproteins contributes to the pathogenesis of coronary artery disease, suggesting that lifestyle modifications as well as pharmacological approaches aimed at reducing postprandial TG levels might help to decrease the cardiovascular risk. The evaluation of postprandial lipemia in the different NAFLD subtypes could help us to: a) determine whether TRLs homeostasis is compromised in metabolic vs. genetic NAFLD and b) confirm the role of metabolic disturbances as risk factors of subclinical atherosclerosis in NAFLD.
In the present proposal, we will investigate subjects who have NAFLD due to the presence of metabolic disturbances only vs. those with NAFLD due to the pro-steatogenic PNPLA3 variant only. We assume that this approach would allow to test the association between the accumulation of fat in the liver and disturbances of postprandial metabolism avoiding biases due to the coexistence of metabolic factors. We hypothesize that the PNPLA3 MM genotype might cause a decrease in VLDL-TG and remnants concentration during the postprandial state while subjects showing NAFLD due to metabolic disturbances might show abnormal dynamics of postprandial TGRs. If proven, this hypothesis might further shed light on the association between metabolic NAFLD and increased ASCVD risk.
The identification of a more maladaptive response to a chronic daily repetitive metabolic challenge, like fat ingestion, in metabolically- compared to genetically- driven NAFLD could allow therapeutic interventions tailored to individual risk profile and mechanism of vascular injury.