A Passion for the Intimate Details of a Protein

September 3, 2014
Researcher Thomas Lagace, PhD, first came across the protein PCSK9 as a postdoctoral fellow, never guessing that it would become the focus of his career.

While starting his post-doc at University of Texas Southwestern Medical Center, he was placed “kind of kicking and screaming,” as he put it, on a research project studying PCSK9. But he quickly became fascinated by the potential impact of this protein as a major regulator of cholesterol metabolism and heart disease risk.

“I thought it was a great thing to be given something to study that you know is important but nobody knows the details of how it works yet,” recalled the Director of the Lipoprotein Receptor Biology Laboratory at the University of Ottawa Heart Institute.

Researchers do know that PCSK9 seems to do more harm than good in the body in terms of blood cholesterol. Dr. Lagace and colleagues found that PCSK9 binds to and marks for destruction the cellular receptors for LDL cholesterol in the liver. When levels of the LDL receptor drop, levels of LDL cholesterol in the bloodstream rise.

In 2013, Lagace and his team found that PCSK9 also binds to LDL in the blood; in fact, about 40 per cent of circulating PCSK9 is bound to LDL. When PCSK9 is bound to LDL in the blood, it cannot bind to the LDL receptor in the liver.

Dr. Lagace thinks PCSK9 is likely part of an ancient feedback mechanism that evolved when calories were scarce and times of fasting were frequent and unpredictable: When blood lipoprotein levels dropped to dangerously low levels, free PCSK9 would bind to and degrade the liver LDL receptors, to keep the remaining lipoproteins circulating and delivering fuel to distant cells in the body.

But in today’s high-calorie environment, he explained, PCSK9 is no longer needed to ensure the delivery of triglycerides and fatty acids throughout the body. “The processes PCSK9 may be trying to protect are already protected, just by the fact that we’re eating a more high-fat, high-cholesterol diet.”

This redundancy of PCSK9 in modern humans makes it an ideal therapeutic target, he added, and studies of people with naturally low levels of PCSK9 show that they seem to suffer no adverse effects over their lifetimes. As a result, drug companies are investing heavily in a new class of drugs that lower LDL cholesterol by blocking PCSK9.

Currently, his lab is planning to confirm their cell-based 2013 results in an animal model. They also hope to map the actual binding site of PCSK9 on the LDL molecule.

This isn’t just an academic exercise. The PCSK9-inhibiting cholesterol drugs currently in development are monoclonal antibodies which must be injected. “We know that LDL inhibits PCSK9’s activity,” said Dr. Lagace. “So, if we learn more about how that happens, we might find a new approach to inhibit PCSK9.” Doing so could make an oral medication possible.