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Chylomicron Metabolism

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Summary

Chylomicron metabolism starts with the absorption of dietary lipids by intestinal epithelial cells. Next, MTP lipidates the chylomicron structural protein, Apo B-48. The lipidated Apo B-48 is now termed a chylomicron, and it is composed primarily of dietary triglycerides. The chylomicron is next secreted from the intestinal epithelia; however, is too large to directly enter the circulation. It is instead absorbed by the lacteals, where it travels by way of the thoracic duct before being emptied into the systemic circulation. Once in the circulation, Apo C-II binds to lipoprotein lipase in capillary beds. Together, they cleave and release the chylomicron’s triglyceride contents, which can then be delivered to the tissue. After the chylomicron’s triglyceride content has been delivered, it is now termed a chylomicron remnant. The resulting remnant is then taken up by the liver via apolipoprotein E.

Mutations in MTP can cause Abetalipoproteinemia.
Homozygous mutations in LPL / Apo C-II can cause Familial Hyperchylomicronemia.
Heterozygous mutations in LPL / Apo C-II or overproduction of VLDL can cause Familial Hypertriglyceridemia.
Mutations in Apo E can cause Familial Dysbetalipoproteinemia.

Key Points

  • Chylomicrons
    • Synthesized in intestinal enterocytes by the lipidation of Apo B-48 by MTP
      • Apo B-48 is the key structural protein for chylomicrons
        • Apo B-48 is synthesized from the same gene as is Apo B-100, but it only has 48% of the sequence after mRNA processing
          • The LDL binding domain is removed, which is why chylomicrons is cleared by Apo E / the Apo E receptor and not Apo B-100 / the LDL receptor (like LDL)
        • There is one Apo B-48 per chylomicron, which gives us a way to count chylomicron numbers via laboratory testing
      • MTP (microsomal triglyceride transfer protein) transfers dietary lipids in the intestinal enterocyte to Apo B-48
        • After lipidation, the Apo B-48 is now referred to as a nascent chylomicron
        • Mutations in MTP lead to abetalipoproteinemia
    • Nascent chylomicrons are released from the enterocyte, absorbed by the lacteals, and emptied into the circulation by way of the thoracic duct
      • Chylomicrons are too large to directly enter the systemic circulation, so they must instead travel via the lymphatic system
      • Chylomicrons therefore bypasses the liver (no first-pass metabolism) and go straight to the body tissues
      • The thoracic duct contains a fatty, milky substance known as “chyle,” so “chylo-microns” refers to microscopic particles in chyle
    • Apo C-II and Apo E are obtained from HDL in the circulation, after which it is termed a “mature” chylomicron
    • Apo C-II binds to lipoprotein lipase (LPL) in capillary beds. Together, they cleave and release triglycerides from the chylomicron, allowing delivery of dietary lipids to the body’s tissues
      • Apo C-II is a cofactor for lipoprotein lipase
      • Triglycerides are cleaved into two free fatty acids and a monoglyceride, which are small enough to be absorbed
      • After delivering its triglyceride contents, the chylomicron is now termed a chylomicron remnant
        • Chylomicron remnants contain mainly dietary cholesterol
      • Homozygous mutations in LPL / Apo C-II can cause familial hyperchylomicronemia
      • Heterozygous mutations in LPL / Apo C-II can cause familial hypertriglyceridemia
    • Apo E binds to hepatic receptors, which facilitates the uptake and clearance of chylomicron remnants
      • Mutations in Apo E can cause familial dysbetalipoproteinemia