Non–High-Density Lipoprotein Cholesterol and Guidelines for Cholesterol Lowering in Recent History

Stanley S. Levinson, PhD


Lab Med. 2020;51(1):14-23. 

In This Article

The Beta-lipoprotein Metabolic Pathways and Dyslipidemias

When lipids are ingested, they are converted to chylomicrons in the intestine, and the chylomicrons are transported via the lymphatics and blood to the liver, where the lipids are removed.[24] During transportation, some chylomicrons are broken down into remnant lipoproteins by lipoprotein lipase (LPL), releasing fatty acids for tissue metabolism. This is a rapid process that takes 2 to 3 hours. Much of the lipid is then transferred to the beta-lipoproteins by incorporation into very-low-density protein (VLDL).

The major beta-lipoprotein metabolic pathways have been known for many years.[24] Knowledge of these pathways is helpful in understanding where drugs act and which target values might be best for which dyslipidemias. A simple illustration of the pathways is shown in Figure 1. Apolipoprotein B-100 (apo B) is the major structural protein in beta-lipoproteins and is needed for VLDL synthesis.[25] VLDLs are synthesized in the liver and released in to the bloodstream. VLDLs are triglyceride-rich and, like chylomicrons, are broken down by LPL to form intermediate-density lipoprotein (IDL) remnants that have approximately equal amounts of cholesterol and triglycerides. These remnants are removed from the bloodstream by receptors that bind apolipoprotein E (apo E)[26] or are converted to LDL by hepatic lipase (HL). LDLs have little or no apo E and are rich in cholesterol. LDL particles containing apo B are removed from the bloodstream by the LDL receptor via endocytosis.[26]

Figure 1.

Beta-lipoprotein pathways. HL indicates hepatic lipase; LPL, lipoprotein lipase; sdLDL, small dense lipoprotein lipase; and R, reaction. Major apolipoproteins (apo) contained in each type lipoprotein particle are indicated in block below the type of particle.

Normally, the removal of LDL particles is the rate-limiting step. The conversion from VLDL to LDL takes 5 to 7 hours, so that generally after a meal, the lipids in chylomicrons have been transferred to LDL in fewer than 10 hours. Thus, an overnight fast is usually appropriate when seeking a fasting specimen in which VLDL-triglyceride is minimal and LDLC is at its steady-state concentration.

Various dyslipidemias can be explained by alterations of the pathway (Figure 1). These include:

Deficiency of LPL: Hypertriglyceridemia may occur if there is a deficiency of LPL or abnormalities in apolipoprotein C2 or C3 (apo C) that inhibit LPL (reaction 1 [R1] in Figure 1). In such a case, VLDL cannot progress to IDL or LDL, and LDLC is usually very low. The triglyceride level usually rises beyond 500 mg per dL.

Dysbetalipoproteinemia: This is a rare familial dyslipidemia in which a person inherits 2 apo E2 genes. In this case, the process cannot progress to form LDL (reaction 2 [R2] in Figure 1), and cholesterol and triglycerides are elevated, from approximately 300 mg per dL to approximately 500 mg per dL. This process is called dysbetalipoproteinemia, type III hyperlipidemia, or broad beta-hyperlipidemia because on electrophoresis, the IDL migrates in a wide (broad) band between the places where the VLDL and LDL should normally migrate. In this case, the process again cannot progress to LDL, and LDLC is usually low.

Hypercholesterolemia: LDLC may be elevated because the LDL receptor may be slow in removing LDL or reduced in number (reaction 3 [R3] in Figure 1), as in familial hypercholesterolemia, so that LDLC may become elevated higher than 160 mg per dL or even 190 mg per dL.

Combined hyperlipidemia (also known as the atherogenic phenotype): This is a type of dyslipidemia in which there is a net overproduction of VLDL. In this case, no specific step is inhibited, so neither cholesterol nor triglyceride levels get extremely high but triglycerides may be moderately increased, in the range of approximately 200 mg per dL to 400 mg per dL. LDLC may or may not be elevated; the HDLC is moderately decreased. The reason the LDLC may not be increased is because in this type of lipidemia, much LDL is synthesized as small dense LDL (sdLDL; Figure 1).[27] sdLDL contains more protein relative to cholesterol, so that although the LDLC may not appear to be elevated, there are nevertheless more LDL particles and there is more apo B.