HDL and atherosclerosis: Insights from inherited HDL disorders


Plasma high density lipoproteins (HDLs) comprise a highly heterogeneous family of lipoprotein particles, differing in density, size, surface charge, and lipid and protein composition. Epidemiological studies have shown that plasma HDL level inversely correlates with atherosclerotic cardiovascular disease. The most relevant atheroprotective function of HDL is to promote the removal of cholesterol from macrophages within the arterial wall and deliver it to the liver for excretion in a process called reverse cholesterol transport. In addition, HDLs can contribute to the maintenance of endothelial cell homeostasis and have potent antioxidant properties. It has been long suggested that individual HDL subclasses may differ in terms of their functional properties, but which one is the good particle remains to be defined. Inherited HDL disorders are rare monogenic diseases due to mutations in gene encoding proteins involved in HDL metabolism. These disorders are not only characterized by extremely low or high plasma HDL levels but also by an abnormal HDL subclass distribution, and thus represent a unique tool to understand the relationship between plasma HDL concentration, HDL function, and HDL-mediated atheroprotection. This article is part of a Special Issue entitled Linking transcription to physiology in lipodomics.


Alex’s Notes: This article caught my eye when I saw the title. For the last 40 years HDL has been recognized as protective against cardiovascular disease, and even most of the general population has an understanding that more HDL is good for health. It is called the “good” cholesterol after all. However, like most things, this understanding of HDL only scratches the surface. The plasma HDL-C measurement common in blood testing is actually a measure of a very complex picture of up to 12 distinct apA-I-containing HDL subclasses. The review at hand aims to look at these various subclasses and the effects of genetic disorders on them to ascertain whether some subclasses may be a more appropriate predictor of cardiovascular risk than HDL-C.

Regardless of subclass, HDL are the most dense and smallest of the lipoproteins, composed primarily of proteins and apolipoprotein A-I (apoA-I) and apoA-II. The best known and most relevant cardio-protective function of HDL is to promote the removal of cholesterol from macrophages (white blood cells) within the arterial wall and deliver it to the liver for excretion in a process called reverse cholesterol transport (RCT). Additionally, HDL can benefit blood vessel integrity by promoting dilation, inhibiting the production of cell adhesion and pro-inflammatory molecules, and favoring repair of the endothelial layer. In fact, HDL has been shown to induce the expression and the activation of endothelial nitric oxide synthase. Finally, HDL has numerous antioxidant properties, not the least of which is the removal of oxidized lipids from LDL.

Given all the above, there is no denying that adequate HDL-C is vital for health. Interestingly, genetically determined low HDL-C levels are not necessarily associated with increased atherosclerosis, and high HDL-C levels are not associated with decreased atherosclerosis. Moreover, these genetic carriers also have abnormal subclass distributions. What can be concluded confidently is that small & dense HDL is beneficial. HDL stands for high-density lipoprotein for a reason, so if you do have your subclasses tested, look for small and dense.

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