Chylomicron Metabolism

For a review of chylomicron metabolism see references [Herz, 1999; Durrington, 1995a; Schumaker, 1992].

The products of fat digestion (fatty acids, monoglycerides, lysophosphatidylcholine and free cholesterol) enter the enterocytes from the mixed micelles, where they are re-esterified in the smooth endoplasmic reticulum.
Long-chain fatty acids (>14 carbon atoms) are esterified with monoglycerides to form triglycerides, and with lysophosphatidylcholine (lysolecithin) to form phosphatidylcholine (lecithin).
Free cholesterol is esterified by the enzyme acyl-coenzyme A (CoA):cholesterol O-acyltransferase.

How are chylomicrons formed?

The triglycerides, phospholipids and cholesteryl esters are combined with an apolipoprotein, known as apolipoprotein (apo) B48, in the enterocyte. The lipoproteins formed in this manner are secreted into the lymph (chyle) and are termed chylomicrons.
They are large (diameter >75 nm; density <950 g/L) and rich in triglycerides, but contain only a relatively small amount of protein (see Figure 2)

Figure 2. Spectrum of plasma lipoprotein particles

Chylomicrons travel through the lacteals to join lymph from other parts of the body, and enter the blood circulation via the thoracic duct.
In addition to cholesterol absorbed from the diet, the chylomicrons may also receive cholesterol that has been newly synthesised in the gut or transferred from other lipoproteins present in the lymph and plasma.
The newly secreted (nascent) chylomicrons receive apo Cs from high-density lipoprotein (HDL), which, in this respect, appears to act as a circulating reservoir; later in the course of chylomicron metabolism, the apo Cs are transferred back to the HDL pool.
The chylomicrons also receive apo E. Unlike most other apolipoproteins, which are synthesised either in the liver or the gut (or both), apo E is exceptional in that it is synthesised (and perhaps secreted) by a large number of tissues: liver, brain, spleen, kidney, lungs and adrenal gland.
Once the chylomicron has acquired the apolipoprotein, apo C-II, it is capable of activating the enzyme lipoprotein lipase (see Figure 3).

Figure 3. Metabolism of chylomicrons, VLDL, IDL and LDL

What is the role of lipoprotein lipase?
Lipoprotein lipase is located on the vascular endothelium of tissues that have a high requirement for triglycerides, for example:

skeletal and cardiac muscle (for energy);
adipose tissue (for storage); and
lactating mammary gland (for milk).

Lipoprotein lipase releases triglycerides from the core of the chylomicron by hydrolysing them to fatty acids and monoglycerides, which are taken up by the tissues locally. In this way, the circulating chylomicron becomes progressively smaller, its triglyceride content decreases and it becomes relatively richer in cholesterol and proteins. As the core shrinks, its surface materials (phospholipids, free cholesterol and apo Cs) become overcrowded and are transferred to HDL. The relatively cholesteryl ester-enriched, triglyceride-depleted product of chylomicron metabolism is known as the chylomicron remnant. The apo B48, present from the time of assembly, remains tightly anchored to the core throughout.

What is the role of the LDL receptor in chylomicron metabolism?
The apo E also remains, and regions of its structure are exposed, permitting catabolism of the chylomicron remnant by the liver. This occurs via the low-density lipoprotein (LDL) receptor, which recognises both apo B100 (see later) and apo E, and via the LDL-receptor-related protein (LRP). Unlike the LDL receptor (discussed in more detail later), LRP is not down-regulated by intrahepatic cholesterol. In addition to its binding site for apo E, LRP also has receptor sites for other proteins.

What are the effects of the LDL receptor and LRP?
The combined effects of the LDL receptor and LRP seem to be the basis of what was once called the 'remnant receptor'. In the case of LRP, however, uptake of the chylomicron remnant is not a simple interaction between apo E and LRP, but also involves the heparan sulphate proteoglycans of the space of Disse, which may trap the chylomicron remnants in the vicinity of LRP. Apo E is inhibited from binding to its receptors earlier in the metabolism of chylomicrons, because its receptor-binding domain is blocked by apo C-III.

How rapidly are the remnants removed?
Remnants are removed from the circulation largely by the liver. In healthy individuals, the chylomicrons and their remnants are removed from the circulation rapidly, within hours of the ingestion of food. After an overnight fast they should have largely disappeared from the circulation.