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Role of LDL cholesterol type in stroke investigated further

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US scientists are delving deeper into the role of a specific form of cholesterol known as very-low-density lipoprotein (VLDL) in various conditions including stroke.

The journey to uncover the influence of cholesterol in cardiovascular health traces back to the pioneering work of François Poulletier de la Salle, who, in 1769, successfully isolated cholesterol from a gallstone

This breakthrough challenged the prevailing belief that blood contained only a single protein and no fat. Subsequent generations of scientists dedicated themselves to defining the molecular formula and structure of cholesterol, as well as understanding its link to the accumulation of plaque in blood vessels and the development of heart disease.

Over the years, medical science has made notable strides in cholesterol management. The first statin, a class of drugs used to lower cholesterol levels, received approval from the Food and Drug Administration (FDA) in 1987, revolutionising the management of high cholesterol and reducing the risk of heart attacks and strokes.

In 2015, the FDA added another powerful tool to cardiologists’ arsenal with the approval of proprotein convertase subtilisin-kexin type 9 inhibitors, offering additional options for patients with persistently high cholesterol levels even after statin treatment.

However, despite these advancements, heart disease remains the leading cause of death in the US, while stroke ranks as the fifth leading cause of death.

While clinical trials have shown some benefit in patients taking proprotein convertase subtilisin-kexin type 9 inhibitors, the absolute risk reduction has been modest, standing at 1.5%. This underscores the pressing need for alternative therapies and a deeper understanding of the various risk factors contributing to heart disease, including heart attacks and strokes.

Dr. Zheng of the Medical College of Wisconsin (MCW), which is leading new research into LPD, says: “It is clear that there is more going on than just what statins and these newer inhibitor drugs can control. 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.”

The new study focuses on the different forms of cholesterol circulating in the bloodstream, with a particular emphasis on what is commonly referred to as “bad cholesterol.”

This type of cholesterol is carried by a protein called apolipoprotein B (apoB), forming structured particles that transport lipids such as cholesterol throughout the bloodstream.

These lipid-rich particles predominantly include very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL), both of which have been targets for cholesterol-lowering drugs.

However, while reducing LDL levels has been a cornerstone of cholesterol management, other members of the same lipoprotein group as LDL have not seen significant reductions with existing treatments.

Dr. Zheng and her team are actively investigating ways to reduce the levels of these less addressed cholesterol-carrying particles, particularly VLDL.

Drawing from her extensive background in lipid metabolism, Dr. Zheng explains her motivation, saying, “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 previous research, Dr. Zheng played a pivotal role in defining a new cellular source of the protein tissue-type plasminogen activator (tPA) and its role in breaking down blood clots and preventing blood vessel blockages.

To assess its potential influence on cholesterol levels, the research team employed a gene-editing technique to halt the production of tPA in liver cells of mice prone to blood vessel plaque formation.

The results were astonishing, as the mice demonstrated elevated levels of lipoprotein-cholesterol. This experiment’s findings were subsequently validated through follow-up studies using human liver cells and a type of rat liver cell that mimicked human liver cells’ production of VLDL.

These and other experimental results have been published in the journal Science, revealing a groundbreaking revelation about tPA’s vital role in regulating blood cholesterol levels and establishing a critical connection between the liver, heart, and blood vessels.

Wen Dai, MD, a research scientist at the Versiti Blood Research Institute, says: “After defining this new role for tPA, we turned our attention to the question of how it changes blood cholesterol levels.”

The liver, a pivotal organ in cholesterol metabolism, primarily contributes to the production of “bad” apoB-lipoproteins by synthesizing VLDL.

Consequently, the research team zeroed in on investigating whether and how tPA impacts the process of VLDL assembly within the liver.

Their findings revealed that tPA competes with microsomal triglyceride transfer protein (MTP), an essential component of VLDL assembly, for binding with apoB. The more tPA present, the less opportunity MTP has to connect with apoB and facilitate the formation of new VLDL particles.

In simple terms, tPA acts as the defensive player intercepting the pass from MTP to apoB on the cholesterol “football field.”

Dr. Zheng notes: “Based on our prior research, we knew it also was critical to look at tPA’s primary inhibitor.”

This inhibitor, known as plasminogen activator inhibitor-1 (PAI-1), is recognized for its ability to impede tPA’s activity. Previous studies have highlighted a correlation between elevated PAI-1 levels in the bloodstream and the development of diseases associated with plaque formation and blockages in blood vessels.

The research team found that higher levels of PAI-1 hindered tPA’s ability to bind with apoB proteins, diminishing tPA’s effectiveness in preventing VLDL production.

Drawing an analogy from the world of sports, PAI-1 may serve as a decoy receiver distracting tPA, allowing MTP to connect with apoB for a significant gain in cholesterol production.

To further substantiate these findings, the team examined individuals with a natural mutation in the gene responsible for PAI-1. As predicted, these individuals exhibited higher tPA levels and lower LDL and VLDL levels compared to their peers from the same community who did not share the same mutation.

Dr. Zheng concludes: “We are investigating therapeutic strategies based on these findings regarding tPA, MTP, and PAI-1. I think we may be able to reduce the residual cardiovascular risk that has persisted even as treatment has advanced.”

By uncovering the crucial role of tPA in regulating cholesterol levels and understanding the intricate interplay between tPA, MTP, and PAI-1, the study opens the door to innovative therapeutic approaches.

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