High density lipoprotein biochemistry
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]; Raviteja Guddeti, M.B.B.S. [3]
Overview
Biochemistry
Structure and Function
- HDL are the smallest of the lipoproteins. They are the densest because they contain the highest proportion of protein. They contain the A class of apolipoproteins.
- The liver synthesizes these lipoproteins as complexes of apolipoproteins and phospholipids, which resemble cholesterol-free flattened spherical lipoprotein particles. They are capable of picking up cholesterol from cells they interact with.
- A plasma enzyme called lecithin-cholesterol acyltransferase (LCAT) converts the free cholesterol into cholesteryl ester (a more hydrophobic form of cholesterol) which is then sequestered into the core of the lipoprotein particle eventually making the newly synthesized HDL spherical. They increase in size as they circulate through the bloodstream and incorporate more cholesterol molecules into their structure.
- Thus it is the concentration of large HDL particles which more accurately reflects protective action, as opposed to the concentration of total HDL particles.[1] This ratio of large HDL to total HDL particles varies widely and is only measured by more sophisticated lipoprotein assays using either electrophoresis, originally developed in the 1970s, or newer Nuclear magnetic resonance (NMR) spectroscopy which was developed in the 1990s.
- HDL particles are not inherently protective. It is only the HDL particles which become the largest (actually picking up and carrying cholesterol) which are protective. There is no reliable relationship between total HDL and large HDL, and more sophisticated analyses which actually measure large HDL, not just total, correlate much better with clinical outcomes.[2]
HDL Metabolism
- 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 .
Cholesterol Ester Transfer Protein (CETP)
- This protein mediates exchange of cholesterol between HDL particles, and triglyceride rich LDL and VLDL in both directions.
- It is normally present in both periphery and liver and functions to channel cholesterol to the liver for uptake and metabolism.
References
- ↑ Kwiterovich PO. The Metabolic Pathways of High-Density Lipoprotein, Low-Density Lipoprotein, and Triglycerides: A Current Review. Am J Cardiol 2000;86(suppl):5L.
- ↑ Tran-Dinh A, Diallo D, Delbosc S; et al. (2013). "HDL and endothelial protection". British Journal of Pharmacology. doi:10.1111/bph.12174. PMID 23488589. Unknown parameter
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