High density lipoprotein physiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ayokunle Olubaniyi, M.B,B.S [2]
Overview
Physiology
HDL Metabolism
The metabolism of HDL can also be described as the Reverse Cholesterol Transport System. HDL serves a mode of transportation for the excess cholesterol from peripheral tissues to the liver.
Synthesis and Uptake of Cholesterol
- HDL consists majorly of apo A-I and/or apo A-II. Both organs synthesize apo A-I while only the liver synthesizes apo A-II.
- Free apo A-I is released into the plasma as nascent HDL. This readily takes up free cholesterol (FC) from peripheral tissues such as fibroblasts and macrophages mediated by either ATP-binding cassette A1 (ABCA1), G1/G4, scavenger receptor class B type 1 (SR-B1), Cyp27A1, caveloin, and passive diffusion, leading to the formation of discoid HDL.
- Apo A-I activates lecithin:cholesteryl acetyltransferase (LCAT) which catalyses the esterification of the free cholesterol bound to the discoid HDL.
aaaaavvvvvvccccccattttttttttttttttttttttttaaaaaaaaaaLCAT
aaaaavvvvvvaaaaaaaaaaaLecithin + Cholesterol ———-> Lysolecithin + Cholesterol ester
Maturation and Transfer of Cholesterol
- The esterified cholesterol moves into the hydrophobic core of the HDL, changing the HDL particle from discoid to spherical (mature HDL). This process also prevents the re-uptake of cholesterol by cells.
- The esterified cholesterol can be delivered back to the liver through a number of routes:
- By the action of cholesterylester transfer protein (CETP) - CETP, secreted in the liver, transfers cholesterol from HDL to the apo B–containing lipoproteins e.g., very low-density lipoprotein (VLDL) or intermediate-density lipoprotein (IDL) to be taken up by the liver.
- HDL particles may be taken up directly by the liver
- Free cholesterol may be taken up directly by the liver
- HDL cholesterol esters may be selectively taken up via the scavenger receptor SR-B1
Catabolism
- Triglyceride lipases degrade these cholesterol-deplete HDL particles into small, dense HDL which after dissociation, release apo A-I (nascent HDL). The apo A-1 then either rapidly reuptakes cholesterol again by ABCA1 to discoid HDL or it is endocytosed in the kidney tubule or cleared via glomerular filtration. These lipoproteins undergo metabolism and subsequent uptake by the liver, primarily by a process mediated by the B,E receptor.
- As mentioned above, the HDL is synthesized in liver and intestines as small nascent particles, composed mainly of phospholipids and apolipoproteins.
- As it travels in the blood it acquires surface components, like more phospholipids, cholesterol and apolipoproteins, from triglyceride depleted chylomicrons and remnants of VLDL.
- As this initial HDL particle contains less amounts of cholesterol, it acquires free unesterified cholesterol from tissues of the liver and arterial walls. This hydrophobic free cholesterol sinks into the center of the HDL particle. The Apolipoprotein A1 acts as a signal protein in mobilizing cholesterol esters from within the cells.
- In the peripheral tissues, the nascent HDL particles interact with a cell surface protein called ABCA1 (also known as cholesterol efflux regulatory protein, CERP). High cholesterol levels induce expression of ABCA1 gene and production of the protein. Mutations of this transport protein gene causes familial HDL deficiencies and Tangier disease. The HDL also accepts cholesterol from triglycerides that has undergone lipolysis.
- Once the cholesterol is acquired by the nascent HDL particles from the peripheral tissues, it gets esterified by a plasma enzyme LCAT (Lecithin-cholesterol acyltransferase). This enzyme is activated by apolipoprotein A1 .