Can this scavenger receptor help solve high cholesterol?

When Pedro Marques was 20, otherwise a thin and healthy teenager, he came face to face with what turned out to be a family health problem: his cholesterol levels were through the roof. Shocked, he started a course of statin therapy – a course he continues today at age 30.

“If I didn’t discover it, if I didn’t start taking medications, I would likely have been an early victim of a vascular incident,” Pedro says.

His problem now sits under a microscope. Pedro earned a Ted Rogers Centre Education Fund award for promising work in the area of cholesterol, inflammation and atherosclerosis. It is, as he calls it, a “personal investment.”

SR-BI protein helps HDL molecules do their work

 

Under the supervision of SickKids senior scientist Sergio Grinstein, the idea is to discover new therapies to prevent or treat atherosclerosis. Pedro’s project focuses on how “good” HDL cholesterol gets transported in our cells, in contrast to “dangerous” LDL cholesterol that is strongly connected to atherosclerosis. HDL, by its nature, is an avenue for the body to redistribute cholesterol and keep arteries clear, therefore, reducing the harmful effects of excessive LDL.

This is a very important area of research, as Ted Rogers Centre executive director Dr. Mansoor Husain says: “There is no bigger predictor of vascular disease than the ratio of HDL to LDL cholesterol in the body.”

Pedro has honed in on the SR-BI protein, a type of scavenger receptor that recognizes and binds HDL, and is very important in promoting HDL’s homeostatic roles. “Learning the physiological role of SR-BI when it comes to HDL cholesterol could open new avenues to prevent and treat inflammation and atherosclerosis.”

Unloading excess cholesterol

Pedro and Sergio took to cells from the liver and adrenal glands, which they discovered to have high levels of SR-BI. (In those glands, cholesterol is used in positive ways, to produce bile and steroid hormones respectively).

Their investigations led to understanding how SR-BI works, how it behaves inside cells, and confirming that it leverages cholesterol for good use. It appears to be the gateway that permits HDL to unload excess cholesterol into a cell to be properly managed – thus removing it from the bloodstream.

Yet what they truly must understand is how cholesterol moves in a cell, and how SR-BI is controlled. How exactly do the body’s cells put that receptor into service?

The key here will be to uncover a way to chemically promote the SR-BI function. If they are able to boost its levels, or make cholesterol bind to it even more effectively, the body could remove far more cholesterol than it can now.

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Image and videos courtesy Pedro Marques.
Video 1:  The blue shows HDL lipoprotein bound to a cell surface, and green is cholesterol the cells have absorbed from the HDL particles, distributing throughout the cell.
Video 2/image at top: SR-BI is in red, while the green and blue represent molecular tools (constructs) they are using to assess how SR-BI behaves.

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