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HDL Dysfunction & It’s Clinical Implication –

High-density lipoproteins (HDLs) represent a class of lipids, very heterogeneous in structure, composition, and biological functions .The density is between 1.063 to 1.210. It has at least 5 sub-types. Normal HDL level in blood should be above 35mg (50-60mg Ideal). When it goes beyond 60 there is not much benefit to accrue and also some surprise findings are there.(Article will be linked)

We know ,HDL carries free cholesterol from peripheral cells, including macrophages and endothelial cells. After reaching the liver, HDL receptors in the hepatocellular surface, metabolize it into bile acid or neutral lipids, which are excreted as bile and feces. This is the much famous Reverse Cholesterol Transport(RCT) and the anti-atherosclerotic effect of HDL .It must be emphasized apart from RCT, it has antioxidant, anti-inflammatory, antithrombotic, and vasodilator actions. Two good reference : One is a book ,that was a surprise . (Review article on HDL) (A text book on HDL )

Structure and shape

HDLs are real complex lipids occurring as pseudomicellar, quasi-spherical lipidomes. It has at-least 80 different binding sites for various proteins and ligands. APO A1 is the major apo-lipoprotein which mediates its action.

In one way, it looks like an International Space Station orbiting in the bloodstream, with multiple docking and releasing points. We are far away, from understanding the role and function of various molecules that get either activated or deactivated either in the circulation or inside the cells. Unlike other sub fractions of lipid, HDL evades routine imaging by NMR or X-ray crystallography. This is one of the reasons we find it to understand this molecule fully.

HDL : The untold story !

Despite the evidence suggesting a clear inverse relationship between HDL cholesterol concentration and the risk for cardiovascular disease, plasma HDL cholesterol levels do not predict the functionality and composition of HDLs. It can change color from good to bad with a drop of a hat in various clinical situations.

Ref : Bonizzi A, Piuri G, Corsi F, Cazzola R, M HDL Dysfunctionality: Clinical Relevance of Quality Rather Than Quantity. Biomedicines. 2021 Jun 25;9(7):729.

Types of HDL dysfunction :

A combination of obesity & diabetes has high chance of pushing this molecule into bad times. There is evidence, (primarily in this setting) HDL undergoes structural changes, and exhibiting pro-inflammatory, pro-oxidant, prothrombotic, and pro-apoptotic properties. (Sounds more ominous than LDL is it not ?)

Glycolysation of HDL

Diabetics results in systemic glycation of all cells or whatever molecule the blood bathes in. We also know the core pathology of diabetic micro angiopathy and basement membrane defects in various target organs are due to this. glycation.

It is very much understandable, HDL also becomes a victim. the glycated HDL is reprogrammed and forgets its good intentions. It not only loses its original function of cholesterol efflux, it ends up facilitating the pro-atherosclerotic forces, by shaking hands with the villain LDL. (Front. Cardiovasc. Med., 27 May 2022 Sec. Lipids in Cardiovascular Disease Eduardo Z. Romo  Volume 9 – 2022) 

A rigid HDL : The key to HDL function lies not only in its structure but also in the shape. It need to be flexible .It is expected to change its shape like a chameleon, while ferrying the cholesterol to liver. It has multiple shapes to choose from, discoid to double helix , spherical as and when required. A rigid HDL struggles to perform its action. Docking and alignment issues with ApO A 1 and A 2 is also contribute to the molecular dysfunction.

Link between HDL and platelet : We are getting more surprises with the multifaceted nature of HDL. Its been demonstrated HDL degrades PAF(platelet activating facto quicker) . hence ,a dysfunctional HDL can change the hematological milieu to pro-coagulant state. European Heart Journal, Volume 44, Issue 16 2023, 1394–1407, 

How to know whether my HDL is functioning all right ?

HDL sub-fractions, APO A 2 are not routinely measured as clinical tool. As of now, there is no practical tests to know it. No worries. If we start thinking about every molecules’ integrity (Just, we have few billions of it ) life will be made miserable. Be-calm, carry on with your work .Trust your HDL, it will remain good for you. Take care of all risk factors and lifestyles that is within your control. This piece is written for the cardiology fellows to understand , the dichotomy between CAD and dyslipidemia.

Final message

*We must admit, as scientists we have had little understanding about HDL. Still, to the public we have passed on a possibly erratic message that HDL is a hero in our fight against CAD. This is purely based on, one of its action i.e., RCT. Maintaining HDL level as per guidelines is good, but the reassurance given by that number can be a superfluous.

*Meanwhile, the concept of Non/dysfunctional HDL can not be taken lightly, since there is considerable evidence to suggest it might transform into a hazardous one in an undefined span of time. This explains the poor correlation between dyslipidemia and CAD risk. More comprehensive research is required to progress further in the field of lipid biology.


1.HDL Dysfunction Is the Answer in the Sphinx’s Riddle?* Juan J. Badimon, PHD, Carlos G. Santos-Gallego,  JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 66, NO. 13, 2015

2.Eren E, Yilmaz N, Aydin O. High Density Lipoprotein and it’s Dysfunction. Open Biochem J. 2012;6:78-93. doi: 10.2174/1874091X01206010078. Epub 2012 Jul 27. PMID: 22888373; PMCID: PMC3414806.

3Camont L et al (2011) Biological activities of HDL subpopulations and their relevance to
cardiovascular disease. Trends Mol Med 17(10):594–603

4Gordon SM et al (2011) High density lipoprotein: it’s not just about lipid transport anymore.
Trends Endocrinol Metab 22(1):9–15

5.Corina Serban, Danina Muntean, Dimitri P Mikhailids, Peter P Toth & Maciej Banach (2014) Dysfunctional HDL: the journey from savior to slayer, Clinical Lipidology, 9:1, 49-59, DOI: 10.2217/clp.13.83

6.Adelheid Kratzer, Hector Giral, Ulf Landmesser, High-density lipoproteins as modulators of endothelial cell functions: alterations in patients with coronary artery disease, Cardiovascular Research, Volume 103, Issue 3, 1 August 2014, Pages 350–361