Mediating role of atherogenic lipoproteins in the relationship between liver fat and coronary artery calcification

Background: Non-alcoholic fatty liver disease (NAFLD) is associated with increased secretion of apoB-containing lipoproteinsand increased risk of coronary heart disease (CHD). ApoB-containing lipoproteins include low-density lipoproteins (LDLs) and triglyceride-rich lipoproteins (TRLs); and since both LDLs and TRLs are causally related to CHD, they may mediate a portion of the increased risk of atherosclerosis seen in people with NAFLD. Methods: : In a cohort of 4161 middle aged men and women, we performed mediation analysis in order to quantify the mediating effect of apoB-containing lipoproteins in the relationship between liver fat and atherosclerosis - as measured by coronary artery calcium score (CACS). Results: : We found plasma apoB to mediate 17.6 % (95 % CI: 11-24) of the association between liver fat and CACS. Plasma triglycerides and TRL-cholesterol (both proximate measures of TRL particles) mediated 22.3 % (95 % CI: 11-34) and 21.6 % (95 % CI: 10-33) of the association respectively; whereas LDL-cholesterol mediated 5.4 % (95 % CI: 2.0-9.4). In multivariable models, the mediating effect of TRL-cholesterol and plasma triglycerides showed, again, a higher degree of mediation than LDL-cholesterol, corroborating the results seen in the univariable models. Conclusions: : We find around 20 % of the association between liver fat and CACS to be mediated by apoB-containing lipoproteins. In addition, we find that TRLs mediate the majority of this effect whereas LDLs mediate a smaller effect. These results explain part of the observed CAD-risk burden for people with NAFLD and further suggest that TRL-lowering may be particularly beneficial to mitigate NAFLD-associated coronary artery disease risk.