Transcytosis: The Hidden Key to Cholesterol and Heart Health

The Cholesterol Paradox

Imagine two scenarios:

1. A person with extremely high LDL cholesterol levels that would alarm most cardiologists, yet their arteries remain pristine.
2. Another individual with seemingly perfect LDL levels who is developing dangerous coronary plaque.

What's happening here? Recent groundbreaking data has shown that some people with astronomically high levels of LDL cholesterol do not appear to be at high risk for heart disease, specifically coronary artery disease.

This phenomenon raises an important question: Why do some individuals with exceptionally high LDL cholesterol and apolipoprotein B (apoB) levels develop no plaque in their arteries, while others, including those with much lower LDL cholesterol and apoB, develop plaque?

Even staunch advocates for LDL and apoB lowering acknowledge this reality. Lipidologist Thomas Dayspring notes, "There are people with high apoB who live long and healthy lives." However, he adds, "I don't know what else is going on in their artery wall."

Let's explore one possible explanation centered around a crucial term: transcytosis.

Understanding Transcytosis

Transcytosis might sound like a maneuver from a science fiction space battle, but it's actually a vital process in our body's cardiovascular system. In simple terms, transcytosis is how substances get past (or perhaps through) the security system of our arteries.

To understand transcytosis, we first need to look at the structure of our blood vessels:

The Endothelial Barrier

Our arteries are lined with cells called endothelial cells. These cells form a barrier between the blood flowing through the vessels and the vessel walls themselves. In a healthy state, this endothelial barrier is tightly knit, not like a coarse chicken wire.

Plaque develops when cholesterol-containing particles, including LDL particles, slip through this endothelial barrier and begin to accumulate in the artery wall. But how do these particles penetrate such a tight barrier?

The Process of Transcytosis

Transcytosis is the process by which a cell, in this case, the endothelial cells lining our arteries, takes up something from the outside (like an LDL particle containing cholesterol), passes it through its interior, and releases it on the other side - in this case, into the artery wall.

While the exact mechanism is not fully understood, we can use an analogy to help visualize it:

Imagine your artery wall is like an exclusive nightclub. Some particles get VIP access, while others are left outside. In this scenario, transcytosis is like having a bouncer escort certain particles (like LDL) through the club and into the VIP section (the artery wall).

Challenging Conventional Wisdom

This perspective on transcytosis challenges a common assumption about plaque development in heart vessels. Many people talk about this process as if having more cholesterol-containing particles (LDL particles) in the blood automatically means more will end up inside the artery wall, like flies getting stuck on flypaper.

However, this idea that more cholesterol-containing particles in your blood directly equates to more flow into your artery walls and increased coronary artery disease risk is a significant assumption - one that may be incorrect or at least incomplete.

Instead, transcytosis is an active, regulated process. A 2025 paper in the journal Atherosclerosis, Thrombosis, and Vascular Biology (ATVB) describes how transcytosis across endothelial cells is the dominant pathway by which cholesterol-containing particles cross the endothelium. This paper suggests that this process might explain currently unexplained differences in coronary disease susceptibility.

The Regulation of Transcytosis

The ATVB paper highlights several fascinating points about how transcytosis is regulated:

1. The Role of LDL Receptors

Contrary to what one might expect, the LDL receptor is not the primary player in the transcytosis of LDL particles across the endothelium in heart blood vessels. While LDL receptors in the coronary endothelium can promote transcytosis, they do so particularly in an inflammatory environment, stimulated by the inflammatory signaling molecule interleukin-1 beta (IL-1β).

This suggests that:

• Low inflammation may lower LDL receptor-mediated transcytosis at the coronary endothelium
• Reduced inflammation could potentially decrease coronary plaque development

2. The Importance of SRB1

A more significant receptor in the transcytosis of LDL particles in the heart is called SRB1. What makes this particularly interesting is that the best-known binding partner for SRB1 is HDL particles, often referred to as "good cholesterol" particles.

Key points about SRB1:

• Higher HDL cholesterol levels are typically associated with better metabolic health
• Studies show that HDL can compete with LDL for SRB1, potentially lowering LDL particle transcytosis
• This competition might be one way that HDL particles protect the heart from coronary artery disease

3. The ALK1 Receptor

The third receptor involved in this process is ALK1. Its activity is regulated by a signaling molecule called BMP9:

• BMP9 reduces ALK1 levels, which in turn reduces transcytosis of LDL particles
• Lower BMP9 levels lead to more LDL transcytosis and increased susceptibility to coronary artery disease
• Importantly, BMP9 levels are low in conditions like metabolic syndrome and type 2 diabetes

This connection between BMP9 and metabolic health may be another way that insulin resistance contributes to or even causes coronary artery disease.

Putting It All Together

To summarize, we have three key receptors involved in transcytosis:

1. LDL receptor: Activated by inflammation
2. SRB1: Inhibited by HDL particles, especially larger HDL particles
3. ALK1: Inhibited by BMP9, which is reduced in insulin resistance

Given this information, if we wanted to design the perfect circumstances to minimize transcytosis across the endothelium and reduce the risk of coronary artery disease despite higher LDL levels, we'd want an environment characterized by:

• Low inflammation
• Lots of HDL, especially large HDL particles
• Insulin sensitivity

Interestingly, this is exactly what we see in a population of lean mass hyper-responders on low-carb, high-fat ketogenic diets. These individuals have very high LDL levels but, as a group, appear to be at much lower cardiovascular risk than conventional thinking would suggest.

Implications and Future Directions

This new understanding of transcytosis and its regulation has significant implications for how we think about cholesterol, heart health, and cardiovascular risk:

1. Beyond LDL Levels: Rather than viewing LDL and apoB levels in isolation, we need to consider the entire metabolic and inflammatory context.

2. Challenging Dogma: This nuanced perspective challenges what some might consider "settled science" (though truly, there's no such thing in science) and forces us to ask better, harder questions.

3. Focusing on the Bigger Picture: If transcytosis is regulated and influenced by factors beyond just LDL levels, shouldn't we be focusing on the broader context? This includes inflammation, HDL and HDL function, and critically, insulin sensitivity, rather than just treating a single number on a lab report.

4. Rethinking Risk Factors: As research continues on lean mass hyper-responders and others with high LDL but possibly low cardiovascular risk, it's becoming clear that the traditional model is incomplete.

5. Personalized Approach: This research suggests that a one-size-fits-all approach to cardiovascular risk assessment and treatment may be inadequate. We may need to develop more personalized strategies that take into account an individual's entire metabolic profile.

6. Potential for New Therapies: Understanding the mechanisms of transcytosis could lead to the development of new therapies that target this process directly, potentially offering new ways to prevent or treat coronary artery disease.

7. Importance of Lifestyle Factors: The role of inflammation and insulin sensitivity in this process underscores the importance of lifestyle factors in heart health. Diet, exercise, stress management, and sleep may all play crucial roles in modulating transcytosis and, by extension, cardiovascular risk.

8. Need for Further Research: While these findings are exciting, they also highlight the need for more research. We need larger, long-term studies to fully understand the implications of these findings and how they might change our approach to cardiovascular health.

Conclusion

The discovery of the regulated nature of transcytosis and its potential role in explaining the paradox of high LDL levels without corresponding cardiovascular risk is a significant step forward in our understanding of heart health. It challenges us to think beyond simple measures of cholesterol and consider the broader metabolic context.

However, it's important to note that this doesn't mean LDL and apoB don't matter. Rather, it suggests that the story is more complex than we previously thought. LDL levels are still important, but they need to be considered alongside other factors like inflammation, HDL function, and insulin sensitivity.

As we continue to research and understand these processes, we may need to rethink our approach to preventing and treating heart disease. Instead of focusing solely on lowering LDL cholesterol, we may need to adopt a more holistic approach that addresses multiple aspects of metabolic health.

For now, these findings remind us of the importance of staying curious, questioning assumptions, and continually seeking a deeper understanding of how our bodies work. They also underscore the value of personalized medicine and the need to consider each individual's unique metabolic profile when assessing cardiovascular risk.

As we move forward, it's clear that the field of cardiovascular health is ripe for new discoveries and paradigm shifts. By staying open to new ideas and continuing to ask challenging questions, we can hope to make significant strides in preventing and treating heart disease in the years to come.

Remember, science is a journey of discovery, not a destination. Today's groundbreaking finding may be tomorrow's starting point for even more exciting discoveries. Stay curious, stay informed, and most importantly, stay healthy.

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