Triglyceride-Rich Lipoproteins and Remnant Cholesterol in Cardiovascular Disease

Abstract

Despite the well-established benefits of statin treatments in lowering low-density lipoprotein cholesterol (LDL-C), a significant residual risk for atherosclerotic cardiovascular disease (ASCVD) remains. Triglycerides (TGs) have long been recognized as potential residual risk factors in this context, but recent studies now disclose the substantial role of TG-rich lipoproteins (TRLs) and cholesterol components of metabolized TRLs (commonly referred to as remnant cholesterol) in atherogenesis, not just TGs alone. Evidence derived through diverse sources, including preclinical studies of pathogenic mechanisms, epidemiologic investigations, and genetic research, has consistently supported the considerable contribution of TRLs and remnant cholesterol in predicting occurrences of ASCVD. As emerging biomarkers for predicting atherosclerosis, they have thus become prioritized therapeutic targets, meant to augment LDL-C lowering efforts in individuals at high risk of ASCVD. However, routine clinical testing for remnant cholesterol and TRLs is still in question, necessitating further research into appropriate treatment plans if levels are elevated. New therapies targeting proteins in TG metabolic pathways, particularly angiopoietin-like protein 3 and apolipoprotein C-III, have shown potential advantages in patients with mild-to-moderate hypertriglyceridemia by reducing blood levels of TGs and remnant cholesterol. The aim of this review is to summarize existing evidence linking elevated TRLs and remnant cholesterol with development of ASCVD and to explore additional guidance for clinical therapy.

Remnant cholesterol as a new lipid-lowering target to reduce cardiovascular events

“…While this calculation offers an approximate estimation of remnant cholesterol levels, it also includes TRL-based cholesterol that has not yet been released as remnants through lipolysis. The advantage of this method is its ability to estimate remnant cholesterol from a standard lipid profile without incurring additional costs or requiring specialized assay equipment [5 ▪ ].…”

“…TRLs are lipoproteins with a core rich in triglycerides, and include chylomicrons, VLDLs and IDLs. There are two primary sources of TRLs: intestine (chylomicrons) and liver (VLDLs) [5 ▪ ]. Triglycerides of exogenous origin are carried in apoB48-containing chylomicrons, while the triglycerides synthesized in the liver are mainly released in VLDL particles containing apoB100.…”

Role of lipoprotein lipase variants in metabolic disorders and cardiovascular diseases

“…These modifications encompass low HDL and low LPL activity in conditions of insulin deficiency, high TG and high VLDLs, normal or low VLDLs and increased HDLs in chronically insulin-treated patients with elevated LPL activity, and low HDLs in untreated T2D patients. In white adipose tissue, heightened LPL activity observed in obese and T2D individuals shares a common characteristic -hypertriglyceridemia, which is positively linked to adverse lipid accumulation in tissues (56,57). Insulin regulates the production and expression of LPL in adipocytes and in the skeletal muscle (58).…”

“…Various regulators influence LPL, including angiopoietin-like (ANGPTL) proteins (such as ANGPTL8, ANGPTL4, ANGPTL3) and certain apolipoproteins (including apolipoprotein A5, apolipoprotein C3, and apolipoprotein C2). These regulators collaboratively modulate LPL activity and the utilization of TG (57,58,82).…”

Revisiting an old relationship: the causal associations of the ApoB/ApoA1 ratio with cardiometabolic diseases and relative risk factors—a mendelian randomization analysis

“…However, some observational studies have found that although maintaining LDL-c levels within a favorable range, the occurrence rate of initial or recurrent atherosclerotic cardiovascular disease (ASCVD) cannot be completely prevented due to residual risk [ 6 – 9 ]. These residual risks mainly originate from the triglyceride-rich lipoproteins (TRLs) and cholesterol components of metabolized TRLs (commonly referred to as remnant cholesterol) [ 10 , 11 ]. Non-high density lipoprotein cholesterol (non-HDL-c) is essentially comprised of remnant cholesterol and LDL-c, encompassing the total cholesterol content of all atherogenic lipoprotein particles [ 12 ].…”