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]
Pathophysiology
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 phospholipid, which resemble cholesterol-free flattened spherical lipoprotein particles. They are capable of picking up cholesterol, carried internally, 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 (the original method developed in the 1970s), or newer NMR spectroscopy, NMR spectroscopy methods, 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.
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 like liver and arterial wall. 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.
HDL Cholesterol and Its Role in Inflammation
In the stress response, serum amyloid A, which is one of the acute phase proteins and an apolipoprotein, is under the stimulation of cytokines (IL-1, IL-6) and cortisol produced in the adrenal cortex and carried to the damaged tissue incorporated into HDL particles. At the inflammation site, it attracts and activates leukocytes. In chronic inflammations, its deposition in the tissues manifests itself as amyloidosis.
Historically, beginning in the late 1970's cholesterol and lipid assays were promoted to estimate total HDL-cholesterol because such tests used to be far less expensive, by about 50 fold, than measured lipoprotein particle concentrations and subclass analysis. Over time, with continued research, decreasing costs, greater availability and wider acceptance of other "lipoprotein subclass analysis" assay methods, including NMR spectroscopy, human studies have continued to show a stronger correlation between human clinically obvious cardiovascular events and quantitatively measured large HDL-particle concentrations.
Recommended Range
The American Heart Association, NIH and NCEP provides a set of guidelines for male fasting HDL levels and risk for heart disease.
| Level mg/dL | Level mmol/L | Interpretation |
| <40 | <1.03 | Low HDL cholesterol, heightened risk for heart disease, <50 is the value for women |
| 40–59 | 1.03–1.52 | Medium HDL level |
| >60 | >1.55 | High HDL level, optimal condition considered protective against heart disease |
More sophisticated laboratory methods measure not just the total HDL but also the range of HDL particles, e.g. "lipoprotein subclass analysis", typically divided into several groups by size, instead of just the total HDL concentration as listed above. The largest groups (most functional) of HDL particles have the most protective effects. The groups of smallest particles reflect HDL particles which are not actively transporting cholesterol, thus not protective.
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.