Scientists from the Karolinska Institute in Sweden report that immune cells in the liver react to high cholesterol levels and engulf excess cholesterol that can otherwise cause damage to arteries. They say their study “Kupffer cells dictate hepatic responses to the atherogenic dyslipidemic insult,” published in Nature Cardiovascular Research, suggests that the response to the onset of atherosclerosis begins in the liver.

In the current study, researchers wanted to understand how different tissues in the body react to high levels of LDL, so called “bad cholesterol,” in the blood. To test this, they created a system where they could quickly increase the cholesterol in the blood of mice.

“Essentially, we wanted to detonate a cholesterol bomb and see what happened next,” says Stephen Malin, PhD, lead author of the study and principal researcher at the department of medicine, Solna, Karolinska Institute. “We found that the liver responded almost immediately and removed some of the excess cholesterol.”

However, it wasn’t the typical liver cells that responded, but a type of immune cell called Kupffer cells that are known for recognizing foreign or harmful substances and engulfing them. The discovery made in mice was also validated in human tissue samples.

“Apolipoprotein-B (APOB)-containing lipoproteins cause atherosclerosis. Whether the vasculature is the initial responding site or if atherogenic dyslipidemia affects other organs simultaneously is unknown. Here we show that the liver responds to a dyslipidemic insult based on inducible models of familial hypercholesterolemia and APOB tracing,” write the investigators.

“An acute transition to atherogenic APOB lipoprotein levels resulted in uptake by Kupffer cells and rapid accumulation of triglycerides and cholesterol in the liver. Bulk and single-cell RNA sequencing revealed a Kupffer-cell-specific transcriptional program that was not activated by a high-fat diet alone or detected in standard liver function or pathological assays, even in the presence of fulminant atherosclerosis.

“Depletion of Kupffer cells altered the dynamic of plasma and liver lipid concentrations, indicating that these liver macrophages help restrain and buffer atherogenic lipoproteins while simultaneously secreting atherosclerosis-modulating factors into plasma. Our results place Kupffer cells as key sentinels in organizing systemic responses to lipoproteins at the initiation of atherosclerosis.

First line of defense

“We were surprised to see that the liver seems to be the first line of defense against excess cholesterol and that the Kupffer cells were the ones doing the job,” says Malin. “This shows that the liver immune system is an active player in regulating cholesterol levels and suggests that atherosclerosis is a systemic disease that affects multiple organs and not just the arteries.”

The researchers hope that by understanding how the liver and other tissues communicate with each other after being exposed to high cholesterol, they can find new ways to prevent or treat cardiovascular and liver diseases.

“Our next step is to look at how other organs respond to excess cholesterol, and how they interact with the liver and the blood vessels in atherosclerosis,” continues Malin. “This could help us develop more holistic and effective strategies to combat this common and deadly disease.”

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