Non-alcoholic fatty liver disease and cardiovascular disease: assessing the evidence for causality

Abstract

Non-alcoholic fatty liver disease (NAFLD) is highly prevalent among individuals with type 2 diabetes. Although epidemiological studies have shown that NAFLD is associated with cardiovascular disease (CVD), it remains unknown whether NAFLD is an active contributor or an innocent bystander. Plasma lipids, low-grade inflammation, impaired fibrinolysis and hepatokines are potential mediators of the relationship between NAFLD and CVD. The Mendelian randomisation approach can help to make causal inferences. Studies that used common variants in PNPLA3, TM6SF2 and GCKR as instruments to investigate the relationship between NAFLD and coronary artery disease (CAD) have reported contrasting results. Variants in PNPLA3 and TM6SF2 were found to protect against CAD, whereas variants in GCKR were positively associated with CAD. Since all three genes have been associated with non-alcoholic steatohepatitis, the second stage of NAFLD, the question of whether low-grade inflammation is an important mediator of the relationship between NAFLD and CAD arises. In contrast, the differential effects of these genes on plasma lipids (i.e. lipid-lowering for PNPLA3 and TM6SF2, and lipid-raising for GCKR) strongly suggest that plasma lipids account for their differential effects on CAD risk. This concept has recently been confirmed in an extended set of 12 NAFLD susceptibility genes. From these studies it appears that plasma lipids are an important mediator between NAFLD and CVD risk. These findings have important clinical implications, particularly for the design of anti-NAFLD drugs that also affect lipid metabolism.

Keywords: Cardiovascular disease; Coronary artery disease; GCKR; Mendelian randomisation; Non-alcoholic fatty liver disease; Non-alcoholic steatohepatitis; PNPLA3; Review; TM6SF2.

Fig. 1

Confounding and mediation. The relationship between NAFLD and CVD, as reported in observational studies, can be explained by confounding or mediation. (a) In confounding, there is a covariate that is (non-causally) associated with NAFLD (green bidirectional arrow) and causally related to CVD (blue arrow), which explains the non-causal association between NAFLD and CVD. In other words, NAFLD is an innocent bystander. (b) In mediation, there is a covariate that is the direct result of NAFLD and causally relates to CVD. In other words, NAFLD is an active contributor to CVD risk, mediated by the covariate. This figure is available as part of a downloadable slideset

Fig. 2

Biologically plausible mechanisms that link NAFLD to the pathogenesis of an atherosclerotic lesion. The combination of endothelial dysfunction and lipoprotein retention in the arterial wall triggers a low-grade inflammatory response, which results in the accumulation of lipid-loaded, monocyte-derived macrophages (‘foam cells’) and the proliferation of smooth muscle cells (SMCs). This newly formed lesion is covered by a thin fibrous cap (FC). The so-called ‘vulnerable plaque’ consists of a necrotic core (NC) and a fibrous cap, which makes it prone to rupture. The subsequent exposure of pro-thrombotic, necrotic material to the blood stream results in acute thrombosis and occlusion of the artery. Simple steatosis (shown on the left side of the liver) and insulin resistance drive overproduction of triacylglycerol-rich VLDL particles. Small-dense LDL (sdLDL) particles, the most atherogenic lipoproteins, are formed by the CETP-mediated exchange of cholesteryl ester (CE) and triacylglycerols (TAG) between VLDL and LDL particles. NASH (shown on the right side of the liver) could theoretically contribute to the low-grade inflammatory environment that is present in the atherosclerotic lesion. Finally, NAFLD (potentially steatosis, NASH or both) contributes to higher circulating PAI-1 levels, which impede the resolution of a thrombus. Other factors that may affect atherogenesis include insulin resistance-induced overproduction of glucose (which promotes monocyte/macrophage adhesion, SMC chemokine secretion and expression of an inflammatory phenotype in macrophages) and fetuin A secretion (which induces low-grade inflammation). This figure is available as part of a downloadable slideset

Fig. 3

Relationship of GCKR, PNPLA3 and TM6SF2 with plasma lipids, type 2 diabetes and CAD. (a) Variants in GCKR, PNPLA3 and TM6SF2 contribute to the development of intrahepatic triacylglycerol (TAG) accumulation by greater hepatic glucose uptake and de novo lipogenesis (GCKR), impaired lipid-droplet remodelling (PNPLA3) and impaired VLDL secretion (PNPLA3 and TM6SF2). As a consequence, they have differential effects on plasma lipid levels. (b–d) Associations of common variants in GCKR, PNPLA3 and TM6SF2 with plasma triacylglycerols (b), LDL-cholesterol (c) and type 2 diabetes (d) (on x-axes) and CAD (on y-axes). Lipid data are derived from [46]; CAD data are derived from [45, 52]; type 2 diabetes data are derived from [50]. Error bars indicate 95% CIs. This figure is available as part of a downloadable slideset