What is the triglyceride (TG) enriched cholesterol particle?

Triglyceride-Enriched Cholesterol Particles

The triglyceride-enriched cholesterol particles are remnant cholesterol, which represents the cholesterol content of all triglyceride-rich lipoproteins (TRLs), including VLDL, intermediate-density lipoprotein (IDL), and chylomicron remnants. 1

Definition and Composition

Remnant cholesterol is calculated as total cholesterol minus LDL cholesterol minus HDL cholesterol, representing all plasma cholesterol not found in LDL and HDL—specifically, cholesterol in all triglyceride-rich lipoproteins. 1

Fasting vs. Nonfasting State

• In the fasting state, remnant cholesterol consists of cholesterol in very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL). 1
• In the nonfasting state, cholesterol in chylomicron remnants is also included, though remnant cholesterol remains mainly cholesterol in VLDL and IDL even postprandially. 1
• This is because triglycerides in all chylomicrons secreted from the intestine and in all VLDL particles secreted from the liver are partially degraded by lipoprotein lipase as soon as these lipoproteins enter the bloodstream. 1

Clinical Significance: Why Cholesterol Content Matters More Than Triglycerides

Triglycerides per se are unlikely to be the cause of atherosclerosis, as triglycerides, unlike cholesterol, can be degraded by most cells in the body and do not accumulate in atherosclerotic plaque. 1

Key Conceptual Framework

• High triglycerides should merely be viewed as a marker of high levels of cholesterol in triglyceride-rich lipoproteins. 1
• The cholesterol to triglyceride content in triglyceride-rich lipoproteins varies, making it more clinically appropriate to estimate/calculate or measure the cholesterol content of triglyceride-rich lipoproteins (remnant cholesterol) rather than relying solely on triglyceride levels. 1
• Practically all triglyceride-rich lipoproteins represent some form of remnants—with the sole exception of triglyceride-rich lipoproteins in individuals with complete lipoprotein lipase deficiency (found in one in a million). 1

Measurement and Clinical Application

Calculation Method

• Remnant cholesterol requires a direct LDL cholesterol assay at triglyceride levels >4.5 mmol/L (400 mg/dL) for accurate estimation in hypertriglyceridemic individuals. 1
• The formula: Remnant cholesterol = Total cholesterol - LDL cholesterol - HDL cholesterol 1

Population Distribution

• In the Copenhagen General Population Study, 21% of adults have elevated remnant cholesterol >1 mmol/L (39 mg/dL). 1
• Elevated remnant cholesterol is largely caused by overweight-obesity and diabetes mellitus, though genetic variation also contributes. 1

Cardiovascular Risk Evidence

Calculated remnant cholesterol is a strong causal risk factor for atherosclerotic cardiovascular disease (ASCVD). 1

Genetic Evidence for Causality

• A 1-mmol/L genetic increase in remnant cholesterol was associated with a 2.8-fold causal risk increase for ischemic heart disease, compared to only 1.4-fold observational risk. 2
• Genetic studies using 185 single nucleotide polymorphisms showed that genetically determined elevated triglyceride levels were strongly associated with ischemic heart disease, even after adjusting for both LDL and HDL cholesterol levels. 2
• Genetic studies demonstrate that elevated triglyceride-rich lipoproteins are causally associated with atherosclerotic cardiovascular disease, whereas low HDL cholesterol per se is not. 2

Epidemiologic Risk Data

• Nonfasting triglycerides >5 mmol/L (440 mg/dL) versus <1 mmol/L (88 mg/dL) were associated with 17-fold and 5-fold increased risk of myocardial infarction in women and men respectively during 27 years of follow-up. 2
• Meta-analyses show that elevated triglycerides confer a relative risk of 1.14 in men and 1.37 in women for cardiovascular disease after adjustment for HDL cholesterol. 2

Mechanism of Action: Fenofibrate's Effect on TG-Rich Particles

Fenofibrate increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-III (an inhibitor of lipoprotein lipase activity). 3

• The resulting decrease in triglycerides produces an alteration in the size and composition of LDL from small, dense particles (which are thought to be atherogenic due to their susceptibility to oxidation) to large buoyant particles. 3
• Fenofibric acid produces reductions in total cholesterol, LDL cholesterol, apolipoprotein B, total triglycerides and triglyceride-rich lipoprotein (VLDL) in treated patients. 3

Common Pitfalls and Clinical Caveats

• Do not rely solely on triglyceride levels to assess cardiovascular risk from triglyceride-rich lipoproteins, as the cholesterol-to-triglyceride ratio varies. 1
• Non-HDL cholesterol (total cholesterol minus HDL cholesterol) is equivalent to LDL and remnant cholesterol combined and should be considered in comprehensive risk assessment. 1
• At present, there is no fully automated, commercial assay available that measures cholesterol in all triglyceride-rich lipoproteins combined, corresponding to calculated remnant cholesterol, though such an assay will likely find future clinical use. 1
• The predictive value of the TG/HDL ratio varies significantly by ethnicity, with black patients with metabolic syndrome or type 2 diabetes potentially not exhibiting high triglyceride levels as commonly as other ethnic groups. 2