High-density lipoprotein (HDL) is a group of proteins that can remove cholesterol from the walls of blood vessels and carry it to the liver for degradation, thus preventing the development of atheroma plaques resulting atherosclerosis. Hence the binomial c-HDL – the result of the union between cholesterol and HDL – is known as ‘good cholesterol’. But there is also a ‘bad cholesterol’: LDL-c, formed by the binding of cholesterol and low-density lipoprotein (LDL). And although LDLs have the mission of transporting cholesterol through the blood, they deposit it in the walls of the arteries and veins – causing atherosclerosis when their amount is excessive. So, having high LDL levels increases your risk of cardiovascular disease. However, it appears that raising HDL levels have no benefit and does not counteract this risk. And why does it happen? The researchers at the Maastricht University might have finally found reason.
As explained by Marjo Donners, director of this research published in the journal Cell Metabolism, “the main message that stems from our study is that the functions of HDLs are not as simple as we thought and seem to depend on a critical form of tissue and of the type of cell in which they are carried out. And in the end, its clinical impact is determined by the balance between its pro and anti-inflammatory actions”.
Numerous studies have shown that HDLs protect against the development of atherosclerosis by removing cholesterol from arteries and veins and thus inhibit the inflammatory process in two very important cell types of blood vessel walls: Endothelial cells and smooth muscle cells. The problem is that this benefit, as suggested by the numerous clinical trials conducted in recent years, appears to have no real effect on cardiovascular health and risk.
In the new study, the authors used an animal model in which they raised HDL levels. And what they observed is that these lipoproteins increased, much, the inflammatory response of the macrophages, that is, the specialized cells of the immune system that are in charge of the phagocytosis of the “foreign bodies” and the invading microorganisms. In fact, macrophages extracted from animals with high levels of HDL showed clear signs of inflammation.
As a result, HDLs protect against atherosclerosis by removing cholesterol and reducing inflammation in endothelial cells and smooth muscle cells in the wall of blood vessels, and promote atherosclerosis by increasing the inflammatory response of macrophages. Two opposing effects seem to negate any cardiovascular health benefits.
And as for its effect on macrophages, why do they do it? For, simply and plainly, to increase protection against pathogens. Although macrophages were very effective in eliminating the invasive bacteria present in animals with high levels of HDL, those mice with low levels of these lipoproteins were condemned to respiratory infections.
As Marjo Donners points out, “the findings suggest that patients with persistent infections or specific immune disorders may benefit from therapies to raise HDL”. Macrophages could also help remove plaque from the atheroma in the early stages of atherosclerosis. But once the disease progresses, its effect would be counterproductive and totally harmful.
“For example, in early atherosclerosis, the proper response of macrophages could lead to a more effective removal of lipids and cell debris, which would alleviate the disease. But in the more advanced stages, the response would be exaggerated and could have a detrimental effect because it would destabilize the plaque”.
In short, more studies are needed to develop HDL-directed therapies that act on cell types and avoid others – such as macrophages, to eliminate any unwanted effects. Future research will have to assess the delicate balance of the effects of HDL on different types of human cells and on different pathologies in order to be able to develop more effective therapeutic strategies”.