Intestinal Absorption of Lipids
Before the formation and secretion of chylomicrons can begin, dietary lipids must be absorbed by intestinal cells, known as enterocytes. The process starts in the intestinal lumen, where dietary triglycerides are broken down by pancreatic and lingual lipases into fatty acids and monoglycerides. These products, along with bile acids, form micelles that transport them across the unstirred water layer to the enterocyte's brush border membrane. From there, the absorption of lipids is mediated by transport proteins such as CD36 and FATP4, and also occurs through passive diffusion.
Formation of Nascent Chylomicrons in the ER
Once inside the enterocyte, a multi-stage process leads to the assembly of chylomicrons in the endoplasmic reticulum (ER). First, the absorbed fatty acids and monoglycerides are re-esterified to form new triglycerides via the monoacylglycerol pathway, a process facilitated by enzymes like MGAT and DGAT. Concurrently, the apolipoprotein B-48 (ApoB48) is synthesized and undergoes lipidation with small amounts of triglycerides and phospholipids. This critical step is aided by microsomal triglyceride transfer protein (MTP), which is essential for transferring lipids to the ApoB48 and forming a primordial, lipid-poor particle.
Chylomicron Core Expansion
After the initial formation, the particle undergoes core expansion. The triglycerides, which are also synthesized in the ER, are added to the primordial chylomicron. This core expansion process, while still not fully understood, is thought to involve the fusion of luminal lipid droplets with the nascent lipoprotein particle. The size of the resulting nascent chylomicron is directly proportional to the amount of fat absorbed and the quantity of triglycerides packaged within it.
Trafficking Through the Golgi Apparatus
Following its synthesis in the ER, the nascent chylomicron is transported to the Golgi apparatus for further processing and maturation. The budding of large, specialized prechylomicron transport vesicles (PCTVs) from the ER is a unique step in this pathway, assisted by proteins like SAR1B. Once docked at the Golgi, the chylomicron undergoes further modifications, including glycosylation of ApoB48 and the acquisition of additional apolipoproteins like ApoA-I, a process that is also influenced by other factors such as the GTPase ARFRP1.
Secretion into the Lymphatic System
Unlike other nutrients that enter the portal circulation and go directly to the liver, mature chylomicrons are secreted from the enterocyte's basolateral membrane into the interstitial fluid. From here, they are too large to pass through the tight junctions of blood capillaries, and instead enter the larger, more permeable lymphatic capillaries known as lacteals. The lymph, now milky-white with chylomicrons and called chyle, travels through the lymphatic system, bypassing the liver, and is ultimately emptied into the venous circulation via the thoracic duct near the subclavian veins. This allows the dietary fat to be delivered to peripheral tissues, such as adipose tissue and muscle, for either storage or immediate energy use.
Chylomicron vs. Very Low-Density Lipoprotein (VLDL) Assembly
| Feature | Chylomicrons (CM) | Very Low-Density Lipoproteins (VLDL) |
|---|---|---|
| Origin | Intestinal enterocytes | Liver hepatocytes |
| Primary Lipid | Dietary triglycerides | Endogenously synthesized triglycerides |
| Primary Apolipoprotein | ApoB48 | ApoB100 |
| Pathway | Exogenous (dietary) | Endogenous (hepatic) |
| Size | Largest lipoprotein (75–600 nm) | Smaller than CM (30–80 nm) |
| Initial Destination | Lymphatic system, bypassing liver | Directly into systemic circulation |
| Function | Transport dietary fats | Transport hepatic fats |
Conclusion
The formation and secretion of chylomicrons is a tightly regulated, multi-step process that is crucial for the absorption and distribution of dietary lipids. From the initial uptake and re-esterification of fatty acids and monoglycerides within the enterocyte to the final release into the lymphatic system, each stage involves specific proteins and cellular compartments. The integrity of this pathway is vital for nutritional health, as defects can lead to malabsorption and other metabolic disorders. A deeper understanding of this process continues to reveal potential therapeutic targets for managing lipid-related diseases. For further reading on the complex regulation of intestinal lipid transport, a review can be found in The intracellular chylomicron highway: novel insights into chylomicron biosynthesis, trafficking, and secretion by Siddiqi and Gorelick.
