Colourised electron micrograph image of a macrophage. Credit: NIH
A new study reveals that immune cells in the liver react to high cholesterol levels and eat up excess cholesterol that can otherwise cause damage to arteries. The findings, published in Nature Cardiovascular Research, suggest that the response to the onset of atherosclerosis begins in the liver.
Immediate response from the liver
In the current study, researchers from Karolinska Institutet wanted to understand how different tissues in the body react to high levels of LDL, commonly 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, lead author of the study and principal researcher at the Department of Medicine, Solna, Karolinska Institutet.
“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 recognising foreign or harmful substances and eating them up. The discovery made in mice was also validated in human tissue samples.
“We were surprised to see that the liver seems to be the first line of defence against excess cholesterol and that the Kupffer cells were the ones doing the job,” says Stephen 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.”
Several organs could be involved
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,” says Stephen Malin. “This could help us develop more holistic and effective strategies to combat this common and deadly disease.”
Researchers have found that previous studies analysing the genomes of people with European ancestry may have reported inaccurate results by not fully accounting for population structure. By considering mixed genetic lineages, researchers at the National Human Genome Research Institute (NHGRI) demonstrated that previously inferred links between a genomic variant for lactase and traits such as a person’s height and low-density lipoprotein cholesterol (LDL-C) level may not be valid.
The study, published in Nature Communications, shows that people with European ancestry, who were previously treated as a genetically homogenous group in large-scale genetic studies, have clear evidence of mixed genetic lineages, known as admixture. As such, the results from previous genome-wide association studies that do not account for admixture in their examinations of people with European ancestry should be re-evaluated.
“By reading population genetics papers, we realised that the pattern of genetic makeup in Europe is too detailed to be viewed on a continental level,” said Daniel Shriner, PhD, staff scientist in the NIH Center for Research on Genomics and Global Health and senior author of the study. “What is clear based on our analysis, is when data from genetic association studies of people of European ancestry are evaluated, researchers should adjust for admixture in the population to uncover true links between genomic variants and traits.”
To look at European genetic ancestry, the researchers collated data in published genetic association studies and generated a reference panel of genomic data that included 19 000 individuals of European ancestry across 79 populations in Europe and European Americans in the US, capturing ancestral diversity not seen in other large catalogues of human genomic variation.
As an example, the researchers investigated the lactase gene, which encodes a protein that helps digest lactose and is highly varied across Europe. Using the new reference panel, they analysed how a genomic variant of the lactase gene is related to traits such as height, body mass index and LDL-C.
When the researchers considered the genetic admixture of the European population in their analysis, they found that the genomic variant of the lactase gene is not linked to height or LDL-C level. In contrast, the same variant does influence body mass index.
“The findings of this study highlight the importance of appreciating that the majority of individuals in populations around the world have mixed ancestral backgrounds and that accounting for these complex ancestral backgrounds is critically important in genetic studies and the practice of genomic medicine,” says Charles Rotimi, PhD, NIH Distinguished Investigator, director of the Center for Research on Genomics and Global Health and senior author of the study.
While the lactase gene is one example of a gene that may be incorrectly linked to some traits based on previous analyses, the researchers say it’s likely that there are other false associations in the literature and that some true associations are yet to be found. Information about how genomic variants are related to different traits helps researchers estimate polygenic risk scores and may give clues about a person’s ability to respond safely to drug treatments.
While the differences in any two people’s genomes are less than 1%, the small percentage of genomic variation can give clues about where a person’s ancestors might have come from and how different families might be related. Information about who a person is biologically descended from, known as genetic ancestry, can give important clues about genetic risks for common diseases.
“Finding true genetic associations will help researchers be more efficient and careful with how further research is conducted,” said first author Mateus Gouveia, PhD, research fellow in the Center for Research on Genomics and Global Health. “We hope that by accounting for mixed ancestries in future genomic analyses, we can improve the predictive value of polygenic risk scores and facilitate genomic medicine.”
The reference panel generated in this study is available to the scientific community for use in other studies, with additional information provided in the paper.
While high levels of low-density lipoprotein (LDL) can be reduced by drugs such as statins, reducing the risk of myocardial infarction and stroke, risk still remains in the form of other cholesterols. New research published in the journal Science describes how manipulating a protein involved in blood clot lysis could help bring cholesterol levels even more under control.
Heart disease remains a leading cause of death worldwide, despite advances in cholesterol-lowering medication such as proprotein convertase subtilisin-kexin type 9 inhibitors, which were approved by the FDA in 2015. One clinical trial following patients taking proprotein convertase subtilisin-kexin type 9 inhibitors demonstrated a benefit while also revealing an opportunity for improvement as the absolute risk reduction was considered modest at 1.5%.
“It is clear that there is more going on than just what statins and these newer inhibitor drugs can control,” says Ze Zheng, MBBS, PhD, MCW assistant professor of medicine. “More therapies are needed, and to get them we need to know more about other sources of risk for heart disease, especially heart attacks and strokes.”
So-called “bad cholesterol” is carried by apolipoprotein B (apoB) which forms well-structured particles with lipids and proteins. These particles serve as stable vehicles for transporting lipids such as cholesterol in the bloodstream. These lipid-rich particles mostly include very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL). Current cholesterol-lowering reduce mainly LDL levels, which though important to control, is not the only risk factor for heart disease. In fact, the other lipoproteins in the same group as LDL are not reduced by much with available treatments. Dr Zheng and her team are investigating how to reduce levels of other members of this family of lipoproteins, especially VLDL.
“With my background in lipid metabolism, I found myself consistently checking lipid levels even during studies regarding blood clot lysis and how an impairment in the body’s ability to remove blood clots affects the risk of blood vessel blockages,” Dr Zheng adds. “I was just naturally curious about it, and I noticed that a protein I was studying may have an effect on the amount of circulating cholesterol.”
In prior research, Dr Zheng has helped define a new cellular source of this protein, tissue-type plasminogen activator (tPA), and its role in breaking down blood clots and preventing blood vessel blockages. To understand its potential influence on cholesterol levels, her team used a gene-editing technique to stop liver cells from producing tPA in mice prone to blood vessel plaque formation. The scientists found that the mice developed increased lipoprotein-cholesterol in this experiment, and then validated the findings in follow-up studies using human liver cells and a type of rat liver cell known to produce VLDL in a way similar to human liver cells. With these and other experimental results, Dr Zheng and her team have demonstrated a new, important role that liver tPA influences blood cholesterol levels while underscoring a meaningful connection between the liver, heart and blood vessels.
“After defining this new role for tPA, we turned our attention to the question of how it changes blood cholesterol levels,” notes Wen Dai, MD, research scientist, Versiti Blood Research Institute.
The liver contributes to the majority of the “bad” apoB-lipoproteins by making VLDL. The team focused on whether and how tPA impacts the process of VLDL assembly in the liver. Microsomal triglyceride transfer protein (MTP) is required for the assembly of VLDL due to its role carrying lipids to the apoB. The scientists determined that tPA binds with the apoB protein in the same place as MTP. The more tPA is present, the fewer opportunities MTP has to connect with apoB and catalyse the creation of new VLDL. Essentially, MTP tries to pass a cholesterol to apoB, but tPA interferes with this pocess.
“Based on our prior research, we knew it also was critical to look at tPA’s primary inhibitor,” Dr. Zheng says.
Plasminogen activator inhibitor-1 (PAI-1) is known to block the activity of tPA. Scientists also have found a correlation between PAI-1 levels in blood and the development of disease due to plaque formation and blockages in blood vessels. The team found that higher levels of PAI-1 reduced the ability of tPA to bind with apoB proteins, rendering tPA less effective at competing with MTP to prevent VLDL production. Returning to the biological gridiron, PAI-1 might be a decoy receiver that distracts tPA until MTP connects with apoB for a big gain. The team studied this interaction in human subjects with a naturally occurring mutation in the gene carrying the code for PAI-1. The researchers found that these individuals, as predicted, had higher tPA levels and lower LDL and VLDL levels than individuals from the same community who did not have the same mutation.
“We are investigating therapeutic strategies based on these findings regarding tPA, MTP and PAI-1,” Dr Zheng notes. “I think we may be able to reduce the residual cardiovascular risk that has persisted even as treatment has advanced.”
A study published in the Journal of the American College of Cardiology found that high-density lipoprotein (HDL) cholesterol, often called ‘good cholesterol’, may not be as effective as scientists once believed in uniformly predicting cardiovascular disease risk among adults of different racial and ethnic backgrounds.
The research found that while low levels of HDL cholesterol predicted an increased risk of heart attacks or related deaths for White adults – a long-accepted association – the same was not true for Black adults. Additionally, higher HDL cholesterol levels were not associated with reduced cardiovascular disease risk for either group.
“The goal was to understand this long-established link that labels HDL as the beneficial cholesterol, and if that’s true for all ethnicities,” said senior author Nathalie Pamir, PhD, an associate professor at Oregon Health & Science University, Portland. “It’s been well accepted that low HDL cholesterol levels are detrimental, regardless of race. Our research tested those assumptions.”
Pamir and colleagues reviewed data from 23 901 participants from the Reasons for Geographic and Racial Differences in Stroke Study (REGARDS). Previous studies that shaped perceptions about ‘good’ cholesterol levels and heart health were conducted in the 1970s through research with a majority of white adult study participants. For the current study, researchers were able to look at how cholesterol levels from Black and White middle-aged adults without heart disease who lived throughout the country overlapped with future cardiovascular events.
Study participants enrolled in REGARDS between 2003–2007 and researchers analysed information collected throughout a 10- to 11-year period. Black and white study participants shared similar characteristics, such as age, cholesterol levels, and underlying risk factors for heart disease, including having diabetes, high blood pressure, or smoking. During this time, 664 Black adults and 951 White adults experienced a heart attack or heart attack-related death. Adults with increased levels of LDL cholesterol and triglycerides had modestly increased risks for cardiovascular disease, which aligned with findings from previous research.
However, the study was the first to find that lower HDL cholesterol levels only predicted increased cardiovascular disease risk for white adults. It also expands on findings from other studies showing that high HDL cholesterol levels are not always associated with reduced cardiovascular events. The REGARDS analysis was the largest US study to show that this was true for both Black and White adults, suggesting that higher than optimal amounts of ‘good’ cholesterol may not provide cardiovascular benefits for either group.
“What I hope this type of research establishes is the need to revisit the risk-predicting algorithm for cardiovascular disease,” Pamir said. “It could mean that in the future we don’t get a pat on the back by our doctors for having higher HDL cholesterol levels.”
Pamir explained that as researchers study HDL cholesterol’s role in supporting heart health, they are exploring different theories. One is quality over quantity. That is, instead of having more HDL, the quality of HDL’s function – in picking up and transporting excess cholesterol from the body – may be more important for supporting cardiovascular health.
The authors conclude that in addition to supporting ongoing and future research with diverse populations to explore these connections, the findings suggest that cardiovascular disease risk calculators using HDL cholesterol could lead to inaccurate predictions for Black adults.
“When it comes to risk factors for heart disease, they cannot be limited to one race or ethnicity,” said Pamir. “They need to apply to everyone.”
