Diabetic mice benefit from increased ‘good’ cholesterol levels

By Dr. Liji Thomas, MDSep 30 2019

According to a new study in the journal Circulation, an artificial increase in the level of ‘good’ cholesterol, or HDL, in diabetic mice with atherosclerosis of their arteries, brought about a reversal of the disease process. HDL is called ‘good’ cholesterol because it keeps fat out of the blood. This study is the first-ever to provide such direct proof that it is possible to reverse atherosclerosis in mice with diabetes by boosting HDL levels in the blood.

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Fats in the blood and cardiovascular disease

Atherosclerosis is a condition in which the arterial walls are affected by high levels of some types of cholesterol – notably the triglycerides, low-density lipoproteins (LDL) and very-low-density lipoproteins (VLDL). The latter two are formed by the combination of cholesterol with various carrier proteins – hence the name ‘lipoproteins’. As the fat accumulates, just below the smooth flat endothelial cells that line the inside of all blood vessels, it causes the cells to bulge out into the hollow space or lumen inside the blood vessels, forming a fatty plaque. Eventually, the endothelial cells may rupture or break apart, allowing blood to come into contact with the plaque. As expected, platelets stick to the rough plaque surface and discharge their contents. This causes the blood to form a clot on the rough surface of the plaque and also attracts other platelets and immune cells.

At the same time, the endothelial damage also recruits inflammatory cells such as immune cells, and these release their own set of powerful cytokines or cell signaling molecules. While inflammation generally tends to heal an injured part of the body, within blood vessels its effects may be disastrous. Both sets of events synchronize to trigger the formation of a web of a fibrous sticky protein called fibrin, trapping more immune cells and platelets, which in turn sets in motion a cascade of events that results in the formation of a fibrin clot. Continuing clotting builds the plaque higher and higher.

The resulting blockage to the flow of blood through the vessel affects the health and function of the tissues downstream of the obstruction. This results in heart attacks and strokes, among other cardiovascular diseases (CVD).

The damage caused is worse in diabetics. When the blood sugar level is high, it (attaches to) glycosylates fats and proteins in the blood, and these bind to and inactivate HDL. This leads to a relative deficiency of HDL function in relieving cells of their lipid burden. Thus the amount of ‘functional HDL’ is severely lowered, though the total amount may be normal or high. These fat-filled cells are damaged and promote even greater inflammation at the site of plaque deposition.

Finding the right target

The importance of this study is to identify the right molecule to target in the treatment of atherosclerosis – namely, HDL or good cholesterol – by increasing its levels to the point where it does not just stabilize but reduces disease processes involved in atherosclerosis. HDL is composed of a protein called apolipoprotein A1 (apoA1) attached to phospholipids, which picks up cholesterol from cells to take them to the liver which can expel them safely from the body.

Most therapies so far have been directed to lower levels of ‘bad’ cholesterol – LDL – the molecular truck that ferries cholesterol from the gut and liver to the cells of the body. LDL does deliver fat to the artery wall cells, just as to other tissues. However, many drugs that reduce the level of LDL cholesterol in attempts to lower the risk of heart disease have not made an impressive dent on the risk of heart attacks and strokes. The effect of such drugs is even less significant in patients with diabetes – who have a twofold risk of death from CVD compared to non-diabetics.

In the face of this resistance, new drugs (such as cholesteryl ester transfer protein inhibitors) were developed to raise HDL levels, in the hope that these two drug categories would complement each other to reduce CVD risk. HDL carries blood from the cells to the liver. However, drug trials in 2016 failed to show the anticipated level of benefit, with any reduction in risk being comparable to that achieved by lowering of cholesterol levels alone.

How HDL affects atherosclerosis

It was obviously time to take a closer look at these matters. As researchers examined the mechanics underlying diabetes, atherosclerosis and inflammation, they started to realize that they needed to evolve a whole new set of criteria by which they could measure the efficacy of HDL-raising drugs. Formerly, it was thought that the level of HDL-C (the HDL present in the bloodstream) reflected the ability of the drug to counter atherosclerosis. Fisher disagrees: he says the cholesterol efflux, or removal of cholesterol from cells, mediated by HDL, gives a true picture of drug efficacy because the presence of cholesterol within cells is the trigger for inflammation.

To assess this, the current experiment focused on raising the levels of apoA1 protein within the bloodstream of diabetic mice. They did this in two ways – they either genetically engineered the mice, or directly injected the protein into the mouse circulation. As the functional HDL levels went up, they found the following changes:

• The bone marrow stopped overproducing inflammatory cells that were being produced in response to cholesterol in the arterial plaques
• The inflammatory markers reflecting immune cell activity in the plaques fell by half
• Atherosclerotic disease markers regressed, or were reversed, by 30% in mice who were already on cholesterol-lowering treatment
• Neutrophils, a type of immune cell in the circulation, were stabilized, preventing inflammatory damage and fibrin webs to the endothelium

Researchers at the NYU School of Medicine who led the study conclude that the molecule called high density lipoprotein (HDL) pulls cholesterol out of lipid-laden cells and thus reduces inflammation. One of them, Edward Fisher, says, “Our study results argue that raising levels of functional good cholesterol addresses inflammatory roots of atherosclerosis driven by cholesterol buildup beyond what existing drugs can achieve.”

For the study, the scientists used a custom-build ‘lite’ HDL molecule called reconstituted HDL.

Reconstituted HDL promises to become the basis for new kinds of functional HDL treatments that finally reduce the residual risk for cardiovascular disease not addressed currently.”

Researcher Tessa Barnett