HDL-Mediated Cholesterol Efflux and Plasma Loading Capacities Are Altered in Subjects with Metabolically- but Not Genetically Driven Non-Alcoholic Fatty Liver Disease (NAFLD)

Abstract

<b>Background</b>. Non-alcoholic fatty liver disease (NAFLD) increases the risk of atherosclerosis but this risk may differ between metabolically- vs. genetically-driven NAFLD. High-density lipoprotein (HDL)-mediated cholesterol efflux (CEC) and plasma loading capacity (CLC) are key factors in atherogenesis. <b>Aims</b>. To test whether CEC and CLC differ between metabolically- vs. genetically-determined NAFLD. <b>Methods</b>: CEC and CLC were measured in 19 patients with metabolic NAFLD and wild-type <i>PNPLA3</i> genotype (Group M), 10 patients with genetic NAFLD carrying M148M <i>PNPLA3</i> genotype (Group G), and 10 controls <i>PNPLA3</i> wild-types and without NAFLD. CEC and CLC were measured ex vivo by isotopic and fluorimetric techniques using cellular models. <b>Results</b>: Compared with Group G, Group M showed reduced total CEC (-18.6%; <i>p</i> < 0.001) as well as that mediated by cholesterol transporters (-25.3% ABCA1; -16.3% ABCG1; -14.8% aqueous diffusion; all <i>p</i> < 0.04). No difference in CEC was found between Group G and controls. The presence of metabolic syndrome further impaired ABCG1-mediated CEC in Group M. Group M had higher plasma-induced CLC than Group G and controls (<i>p</i> < 0.001). <b>Conclusions</b>: Metabolically-, but not genetically-, driven NAFLD associates with dysfunctional HDL-meditated CEC and abnormal CLC. These data suggest that the mechanisms of anti-atherogenic protection in metabolic NAFLD are impaired.