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VLDL Metabolism

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Summary

VLDL stands for very low density lipoprotein, and it delivers endogenous lipids (mainly triglycerides) throughout the body. It is synthesized in the liver, and its synthesis begins with MTP’s lipidation of the structural protein Apo B-100. The lipidated Apo B-100 is now called VLDL, which can now be secreted into the bloodstream. Next, Apo C-II on the VLDL particle binds to lipoprotein lipase in capillary beds. Together, they release triglycerides from VLDL and deliver them to tissues as free fatty acids.

Once VLDL loses some of its triglycerides, it is now termed IDL (intermediate density lipoprotein, which is also known as a VLDL remnant). IDL is then either taken up by Apo E in the liver, or it is converted into LDL by hepatic lipase.

LDL (low density lipoprotein) is rich in cholesterol, and LDL’s main function is to deliver endogenous cholesterol to the rest of the body. To do this, LDL’s Apo B-100 binds to the LDL receptor. This facilitates the endocytosis of the LDL particle, and hence the delivery of its endogenous cholesterol contents.

Key Points

  • VLDL
    • Synthesized in the liver by the lipidation of Apo B-100 by MTP
      • VLDL carries endogenous lipids
        • Contrast with chylomicrons, which carry dietary (i.e. exogenous) lipids
      • Apo B-100
        • Apo B-100 is VLDL's key structural protein
          • There is one Apo B-100 per VLDL particle, which gives us a way to count VLDL numbers via laboratory testing
        • Apo B-100 also contains an LDL receptor-binding domain
      • MTP
        • MTP stands for microsomal triglyceride transfer protein
    • "Nascent" VLDL is released from the liver and emptied into the circulation
      • Apo C-II and Apo E are obtained from HDL in the circulation, after which it is termed “mature” VLDL
    • Apo C-II binds to lipoprotein lipase (LPL) in capillary beds. Together, they cleave and release triglycerides from the VLDL, allowing delivery of endogenous 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 VLDL is now termed IDL (i.e. a VLDL remnant)
  • IDL
    • IDL contains mostly cholesterol, but there are still some triglycerides left (which is why the density is “intermediate”)
    • Two fates
      • Apo E binds to hepatic receptors, which facilitates the uptake and clearance of IDL
      • Hepatic lipase further metabolizes IDL to LDL
        • Releases the remaining triglcyerides (which is why the density is “low” afterwards)
    • IDL metabolism is therefore a key regulatory step in this pathway
  • LDL
    • LDL contains mostly cholesterol; it’s main function is to deliver dietary cholesterol
      • LDL cholesterol is termed “bad cholesterol” because it also delivers cholesterol to atherosclerotic plaques
    • LDL is taken up by Apo B-100 binding to the LDL receptor
      • LDL is endocytosed, which allows delivery of cholesterol


Diseases

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.
Mutations in the LDL receptor / Apo B-100 can cause Familial Hypercholesterolemia.

Misc

"Low" vs "high" density refers to triglyceride content. Low density = high triglycerides and high density = low triglycerides. Low density lipoproteins contain relatively less triglycerides and relatively more cholesterol.