Transcitose de LDL: o elo perdido na formação da aterosclerose

For decades, the dominant narrative about cholesterol was simple: the higher the LDL in the blood, the higher the risk of heart attack. But recent evidence is challenging this reductionist view. The formation of atherosclerotic plaques depends not only on the concentration of LDL in the blood, but on how much of this LDL manages to cross the endothelial wall and accumulate in the arterial intima. This is where a process called transcytosis comes in, an active, regulated and highly selective mechanism that transports LDL particles into the vessel wall. Contrary to what many people imagine, the endothelial barrier is not a sieve through which LDL simply escapes passively. LDL needs to be internalized by endothelial cells and translocated by intracellular vesicles – a process reminiscent of VIP transport of a substance through the safety of the blood vessel. This transport is mediated mainly by vesicles called caveolae, and involves key proteins such as caveolin-1, as well as specific receptors such as LDLR, SR-B1 and ALK1. The importance of transcytosis becomes clear when we observe that individuals with the same level of plasma LDL can have very different risks of cardiovascular disease. The explanation? The difference in the rate of transcytosis. In other words, it is not enough to know how much LDL is circulating – we need to know how much is being transported into the arterial wall. Several factors increase LDL transcytosis: 1. Inflammation: The cytokine IL-1β increases the activity of the LDLR receptor, stimulating transcytosis. In inflammatory environments, there are more active receptors, facilitating the entry of LDL into the vessel wall. 2. Low HDL: The SR-B1 receptor, in addition to transporting LDL, also interacts with HDL particles. HDL competes with LDL for this receptor, inhibiting its transport. In other words, the more HDL, the lower the LDL transcytosis. 3. Insulin resistance: The ALK1 receptor is regulated by a protein called BMP9, which is reduced in people with metabolic syndrome or type 2 diabetes. When BMP9 levels fall, ALK1 activity increases, promoting more transcytosis. Therefore, increased transcytosis is a direct reflection of a dysfunctional metabolic environment—one characterized by chronic inflammation, low HDL levels, and insulin resistance. This explains why not all high LDL is pathological. Lean hyperresponders on ketogenic diets, for example, often have high LDL but low levels of inflammation, high HDL, and excellent insulin sensitivity—the very scenario that inhibits transcytosis and, consequently, reduces the risk of plaque formation. This new understanding points to a different paradigm for atherosclerosis prevention. Rather than focusing exclusively on lowering LDL, we should prioritize strategies that modulate transcytosis and promote a healthy metabolic environment. This includes: • Reducing chronic inflammation through an anti-inflammatory diet low in ultra-processed foods; • Increasing HDL with regular physical activity and consumption of good fats; • Improving insulin sensitivity through low-carb, ketogenic or intermittent fasting diets; • Reducing oxidative stress and getting adequate sleep, which directly impact endothelial function. In short, transcytosis is the missing link between LDL and atherosclerotic plaque formation. Ignoring it is like judging the risk of a fire based solely on the presence of fuel, without considering whether or not there is a spark. LDL is necessary, but without active transcytosis, there is no accumulation in the arterial wall. The future of metabolic cardiology needs to look beyond the numbers and consider the context. References: BOLANLE, I. O.; DE LIEDEKERKE BEAUFORT, G. C.; WEINBERG, P. D. Transcytosis of LDL Across Arterial Endothelium: Mechanisms and Therapeutic Targets. Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 45, p. 468–480, apr. 2025. DOI: 10.1161/ATVBAHA.124.321549. NORWITZ, N. Why Some People with Sky-High LDL Don’t Get Heart Disease. Substack, 2025. Available at: https://staycuriousmetabolism.substac.... Accessed on: 17 April. 2025.