Chylomicron metabolism

Chylomicrons are assembled in intestinal mucosal cells and carry dietary  (exogenous) TAG, cholesterol, fat-soluble vitamins, and cholesteryl esters to the peripheral tissues (Fig. 1). [Note: TAG account for close to 90% of the lipids in a chylomicron.]

Figure 1: Metabolism of chylomicrons. Apo B-48, apo C-II, and apo E are apolipoproteins found as components of plasma lipoprotein particles. The particles are not drawn to scale. TAG = triacylglycerol; C = cholesterol; CE = cholesteryl ester; HDL = high-density lipoprotein.

1. Apolipoprotein synthesis: Apo B-48 is unique to chylomicrons. Its synthesis begins on the rough ER (RER), and it is glycosylated as it moves through the RER and Golgi. [Note: Apo B-48 is so named because it constitutes the N-terminal 48% of the protein encoded by the gene for apo B. Apo B-100, which is synthesized by the liver and found in VLDL and LDL, represents the entire protein encoded by this gene.

Posttranscriptional editing  of a cytosine to a uracil in intestinal apo B-100 messenger RNA (mRNA) creates a nonsense (stop)  codon, allowing translation of only 48% of the mRNA.]

2. Chylomicron assembly: Many enzymes involved in TAG, cholesterol,

and phospholipid synthesis are located in the SER. Assembly of the apolipoprotein and lipid into chylomicrons requires microsomal triglyceride transfer protein ([MTP]), which loads apo B-48 with lipid. This occurs before transition from the ER to the Golgi, where the particles are packaged in secretory vesicles. These fuse with the plasma membrane releasing the lipoproteins, which then enter the lymphatic system and, ultimately, the blood. [Note: Chylomicrons leave the lymphatic system via the thoracic duct that empties into the left subclavian vein.]

3. Nascent chylomicron modification: The particle released by the intestinal mucosal cell is called a nascent chylomicron because it is functionally incomplete. When it reaches the plasma, the particle is rapidly modified,  receiving apo E (which is recognized by hepatic receptors) and apo C.

The latter includes apo C-II, which is necessary for the activation of lipoprotein lipase (LPL), the enzyme that degrades the TAG contained in the chylomicron. The source of these apolipoproteins is circulating HDL  (see Fig. 1). [Note: Apo C-III on TAG-rich lipoproteins inhibits LPL.]

4. Triacylglycerol degradation by lipoprotein lipase: LPL is an extracellular enzyme that is anchored to the capillary walls of most tissues but predominantly those of adipose tissue and cardiac and skeletal muscle.

The adult liver does not express this enzyme. [Note: A hepatic lipase is found on the surface of endothelial cells of the liver. It plays a role in TAG degradation in chylomicrons and VLDL and is important in HDL metabolism.] LPL, activated by apo C-II on circulating chylomicrons, hydrolyzes the TAG in these particles to FA and glycerol.

The FA are stored (in adipose) or used for energy (in muscle). The glycerol is taken up by the liver, converted to dihydroxyacetone phosphate (an intermediate of glycolysis), and used in lipid synthesis or gluconeogenesis. [Note: Patients with a deficiency of LPL or apo C-II  (type I hyperlipoproteinemia or familial chylomicronemia) show a dramatic accumulation (≥1,000 mg/dl) of chylomicron-TAG in the plasma (hypertriacylglycerolemia) even in the fasted state. They are at increased risk for acute pancreatitis. Treatment is the reduction of dietary fat.]

5. Lipoprotein lipase expression: LPL is synthesized by adipose tissue and by cardiac and skeletal muscle. Expression of the tissue-specific isozymes is regulated by nutritional state and hormonal level. For example, in the fed state (elevated insulin levels), LPL synthesis is increased in adipose but decreased in muscle tissue. Fasting (decreased insulin) favors LPL synthesis in muscle. [Note: The highest concentration of LPL is in cardiac muscle, reflecting the use of FA to provide much of the energy needed for cardiac function.]

6. Chylomicron remnant formation: As the chylomicron circulates, and >90% of the TAG in its core is degraded by LPL, the particle decreases in size and increases in density. In addition, the C apolipoproteins (but not apo B or E) are returned to HDL. The remaining particle, called a remnant, is rapidly removed from the circulation by the liver, whose cell membranes contain lipoprotein receptors that recognize apo E (see Fig.  1). Chylomicron remnants bind to these receptors and are taken into the hepatocytes by endocytosis. The endocytosed vesicle then fuses with a lysosome, and the apolipoproteins, cholesteryl esters, and other components of the remnant are hydrolytically degraded, releasing amino acids, free cholesterol, and FA. The receptor is recycled.