Newly discovered ‘molecular guardian’ keeps cholesterol in check

human heart
New insight into how cells respond to high cholesterol levels could advance the search for new ways of protecting heart health.

Harvard University researchers have identified a protein that helps keep cellular cholesterol levels under control. They call it a “molecular guardian” and it could become a target in the treatment of disorders that involve cholesterol metabolism.

“The cell must guard against any rise in cholesterol—it cannot tolerate levels that are too high or too low," said senior author Gökhan Hotamisligil in a statement. Excess cholesterol can cause toxicity, inflammation and ultimately cell death.

While the cellular signals used to respond to low cholesterol are well known, the researchers said, it has been unclear how cells tackle high cholesterol. They looked for answers in the endoplasmic reticulum, an organelle surrounded by a membrane that is low in cholesterol and would be particularly vulnerable to a spike in cholesterol, Hotamisligil said.

The search turned up a few molecules that might be involved in cholesterol regulation, but the team zeroed in on the protein Nrf1, the levels of which increase when cellular cholesterol rises. When Nrf1 is blocked in mice, the liver “dramatically enlarged” and became inundated with cholesterol, they said.

Specifically, Nrf1 regulates high cholesterol by binding directly to it. This binding prompts a series of processes in the cell that curb inflammation and stimulate cholesterol removal. The findings are published in the journal Cell.

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High cholesterol has no symptoms, but it can lead to atherosclerosis, or cholesterol buildup in the arteries, which can cause chest pain, heart attack or stroke. It is usually managed with dietary changes, exercise and medications like statins or PCSK9 inhibitors.

A recent study found that a PCSK9 inhibitor may be able to immunize people against developing high cholesterol and atherosclerosis. The vaccine induces the production of antibodies that inhibit PCSK9, allowing the body to eliminate LDL, or “bad,” cholesterol.

But scientists are still looking for alternative methods for managing high cholesterol, and the Harvard scientists believe the insight from their research could advance the field. "This discovery really teaches us a lot about how cells maintain cholesterol homeostasis," Hotamisligil said. "Now, we demonstrate that there is a molecular yin-yang—formed by NRF1 and SREBP2—that together keep cellular cholesterol within a safe, narrow range. That's an exciting finding that could have broad, new therapeutic applications."