If one were to only listen to news sound bites, then their impression of carbohydrate molecules would be that they are either needed to sustain athletic endurance or that they are the root of all evil, destroying healthy lives—which doesn’t leave much grey area. Thankfully, scientists are inclined to block out some of the popular “noise,” focusing on the biological role of sugar molecules in normal and disease pathology. In that vein, investigators at Washington University School of Medicine in St. Louis (WUSM) have just provided new evidence showing how a natural sugar called trehalose revs up the immune system's cellular housekeeping abilities.
Interestingly, these charged-up housecleaners can reduce atherosclerotic plaque that has built up inside arteries—a hallmark of cardiovascular disease that leads to an increased risk of heart attack. Findings from this new study were published recently in Nature Communications in an article entitled “Exploiting Macrophage Autophagy-Lysosomal Biogenesis as a Therapy for Atherosclerosis.”
The researchers looked at the role of the immune system in mediating cellular pathways that are involved in potentially reversing atherosclerotic plaque formation.
“We are interested in enhancing the ability of these immune cells, called macrophages, to degrade cellular garbage—making them supermacrophages,” explained senior study investigator Babak Razani, M.D., Ph.D., assistant professor of medicine at WUSM.
Macrophages are immune cells responsible for cleaning up many types of cellular waste, including misshapen proteins, excess fat droplets, and dysfunctional organelles—specialized structures within cells.
“In atherosclerosis, macrophages try to fix damage to the artery by cleaning up the area, but they get overwhelmed by the inflammatory nature of the plaques,” Dr. Razani noted. “Their housekeeping process gets gummed up, so their friends rush in to try to clean up the bigger mess and also become part of the problem. A soup starts building up—dying cells, more lipids. The plaque grows and grows.”
In the current study, the investigators showed that mice prone to atherosclerosis had reduced plaque in their arteries after being injected with trehalose. The sizes of the plaques measured in the aortic root were variable, but on average, the plaques measured 0.35 mm2 in control mice compared with 0.25 mm2 in the mice receiving trehalose, which translated into a roughly 30% decrease in plaque size—a statistically significant difference.
Remarkably, the trehalose effect disappeared when the mice were given the sugar orally or when they were injected with other types of sugar, even those with similar structures.
Found in plants and insects, trehalose is a natural sugar that consists of two glucose molecules bound together. It is approved by the FDA for human consumption and often is used as an ingredient in pharmaceuticals. Past work by many research groups has shown trehalose triggers an important cellular process called autophagy, or self-eating, a self-degradative process in cells. But just how it boosts autophagy has been unknown.
However, the WUSM team was able to show that trehalose operates by activating a transcription factor called TFEB. Activated TFEB goes into the nucleus of macrophages and binds to DNA. That binding turns on specific genes, setting off a chain of events that results in the assembly of additional housekeeping machinery—more of the organelles that function as garbage collectors and incinerators.
“Trehalose is not just enhancing the housekeeping machinery that's already there,” Dr. Razani concluded. “It's triggering the cell to make new machinery. This results in more autophagy—the cell starts a degradation fest. Is this the only way that trehalose works to enhance autophagy by macrophages? We can't say that for sure—we're still testing that. But is it a predominant process? Yes.”