Liver's cholesterol-eating cells unveiled by researchers

By Lisa Marie Basile | Fact-checked by Davi Sherman
Published March 19, 2024

Key Takeaways

  • A recent study found that Kupffer cells—immune cells of the liver—may modulate the body’s response to cholesterol, potentially preventing the development of atherosclerosis (which can lead to stroke, heart attack, vascular dementia, and erectile dysfunction).

  • Researchers found that Kupffer cells can help restrain and buffer atherogenic lipoproteins while simultaneously secreting atherosclerosis-modulating factors into plasma. Kupffer cells may have an ambivalent function. Experts say that more research is needed.

A March 11 study published in Nature Cardiovascular Research explores how specific immune cells of the liver—known as Kupffer cells—may act as an early agent against atherosclerosis-causing lipoproteins. 

In the study, researchers introduced high cholesterol levels in mice to see how the liver would respond. The findings were also confirmed in human tissue samples. 

As the authors note, lipoproteins containing apolipoprotein-B (APOB) can cause atherosclerosis: plaque buildup within the arteries. An estimated 50% of Americans between the ages of 45 and 84 have atherosclerosis but aren’t aware of it. Over time, this plaque causes the arteries throughout the body, resulting in conditions like coronary artery disease, renal artery stenosis, vertebral artery disease, and carotid artery disease. Blood clots resulting from burst plaque can cause blockages and further complications, including stroke, heart attack, vascular dementia, erectile dysfunction, or limb loss.[][]

In addition to atherosclerosis, APOB is also linked to other pathologies. APOB is produced in the liver itself, a main element in the creation of low-density lipoproteins (LDLs), which carry plaque-causing cholesterol through the bloodstream. APOB allows LDLs to attach tocell receptors,  particularly in the liver. Once attached, the receptors are broken down to release cholesterol. The cholesterol is then used by the cell, stored, or removed from the body.[]

So, what do the Kupffer cells do? “You get these large fluffy fatty cells called foam cells. They typically die and leave a trail of destruction. Your immune system comes in and puts a plaque on top of it. So, Kupffer cells' macrophage-like cells help with gobbling up things that come their way,” explains Yu-Ming Ni, MD, a board-certified cardiologist and lipidologist at MemorialCare Heart & Vascular Institute at Orange Coast Medical Center in Fountain Valley, CA.

Prior research notes that Kupffer cells play “a critical role in maintaining liver functions. Under physiological conditions, they are the first innate immune cells and protect the liver from bacterial infections.”[] 

To further validate the role of the Kupffer cells, the study’s researchers deleted the Kupffer cells in mice, which altered plasma and liver lipid concentrations. This indicated, the authors write, that the cells “help restrain and buffer atherogenic lipoproteins while simultaneously secreting atherosclerosis-modulating factors into plasma.”[]

Specifically, the deletion of Kupffer cells increased plasma cholesterol and triglyceride levels in certain mice and decreased cholesterol and triglyceride content in the livers of other mice.[]

As a result, the authors believe that Kupffer cells have a “potentially ambivalent function,” in that they can “express and secrete pro-inflammatory and anti-inflammatory factors into plasma but, at the same time, retain circulating pro-atherogenic APOB lipoproteins…This raises questions regarding the overall long-term effects of KCs [Kupffer cells] on atherosclerosis development. Such questions will be difficult to address,” the authors summarize.[]

Echoing this ambiguity, Dr. Ni says, “Part of me wonders whether this is a good thing—the clearing of cholesterol and metabolizing and degrading it—or if this could be a bad thing. It [may] spark a chain reaction that can lead to liver disease.” He cites fatty liver disease, which can predispose people to inflammation-causing cirrhosis.

Dr. Ni says that more questions must be answered before the findings translate into clinical practice. “I think what's worth discussing is [that] the way in which cholesterol plaques form in our blood vessels is driven by our immune response to inflammatory stimulants, particularly when you have these oxidized phospholipids and cholesterol particles that induce immune response,” he says. “I think this needs to be investigated further, to elucidate whether we should be thinking of immune response in the liver.”

As Dr. Ni notes, the study’s findings lead to more questions. Study author Stephen Malin tells MDLinx, “What we didn’t know was how tissues respond over time. Does this bad cholesterol first start building plaques in your arteries, or does it begin causing damage throughout the body everywhere all at once? This is important, because we have traditionally seen atherosclerosis as a disease that is focused on blood vessels. If many organs are being affected, then we need to consider the disease in a more holistic perspective.”[]

“What our experiments are hinting at is that when we have too much of this bad cholesterol, it is not just your blood vessels that will get damaged, but also your liver [that] will be affected at the same time,” Malin adds. “Our next steps are to look at all the other organs and see if they are responding, too. We hope that once we know this, we can try to figure out how the cells and tissues are talking to each other after being insulted, and then find out what this conversation means for cardiovascular and liver diseases.”

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