The Forgotten Lipids: Triglycerides, Remnant Cholesterol, and Atherosclerotic Cardiovascular Disease Risk

Abstract

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death worldwide. Low-density lipoprotein cholesterol (LDL-C) is a well-established mediator of atherosclerosis and a key target for intervention for the primary and secondary prevention of ASCVD. However, despite substantial reduction in LDL-C, patients continue to have recurrent ASCVD events. Hypertriglyceridemia may be an important contributor of this residual risk. Observational and genetic epidemiological data strongly support a causal role of triglycerides (TGs) and the cholesterol content within triglyceride-rich lipoproteins (TGRLs) and/or remnant cholesterol (RC) in the development of ASCVD. TGRLs are composed of hepatically derived very low-density lipoprotein and intestinally derived chylomicrons. RC is the cholesterol content of all TGRLs and plasma TGs serve as a surrogate measure of TGRLs and RC. Although lifestyle modification remains the cornerstone for management of hypertriglyceridemia, many novel drugs are in development and have shown impressive efficacy in lowering TG levels. Several ongoing, randomized controlled trials are underway to examine the impact of these novel agents on ASCVD outcomes. In this comprehensive review, we provide an overview of the biology, epidemiology, and genetics of TGs and ASCVD; we discuss current and novel TG-lowering therapies under development.

Figure 1.

Triglyceride-rich lipoprotein metabolism and mechanism of atherosclerosis. TGRLs are derived from an endogenous pathway through the liver and an exogenous pathway through the small intestine. In the endogenous pathway, VLDL is produced in the hepatocytes from FFAs derived from the circulation or newly synthesized in the liver. A variety of apolipoproteins are added to the surface of the nascent VLDL particle during secretion, including apoB100, apoCII, apoCIII, and apoE. Once VLDL is secreted into the plasma, LPL along the luminal surface of capillaries hydrolyzes the TGs within the core of VLDL into FFAs generating VLDL remnant/IDL particles and lipolytic products. The FFAs are taken up by muscle and adipose tissue. The IDL particles are further catabolized into LDL and lipolytic products by HL. In the exogenous pathway, dietary fats are absorbed by enterocytes and incorporated into apoB48 containing chylomicrons, which are then secreted into the lymphatic system and enter the circulation, where they acquire apoCII, apoCIII, and apoE. In the circulation, LPL along the luminal surface of capillaries hydrolyzes the TGs within the core of chylomicrons into FFAs generating chylomicron remnant particles. The FFAs can be taken up muscle and adipose tissue. Endogenous and exogenous remnants are cleared from the circulation by hepatic uptake via the LDL receptor, LRP1, and HSPG receptor. LPL plays a key role in TGRL metabolism and is highly regulated by various proteins. ANGPTL 3, ANGPTL 4, and apoCIII inhibit LPL activity, whereas apoCII is an important activator of LPL activity. TGRL and their remnants readily penetrate the arterial wall and can be taken up by scavenger receptors on macrophages directly without oxidative modification, leading to formation of foam cells and atherosclerotic plaque development. ANGPTL, angiopoietin-like protein; HL, hepatic lipase; LRP1, LDL receptor related protein-1; HSPG, heparan sulfate proteoglycan.