Biologists have proposed a new way to lower blood cholesterol levels
Excess cholesterol is fraught with cardiovascular disease, and those are the leading cause of mortality. With this in mind, the authors of the new paper investigated the metabolism of cholesterol and described a previously unknown stage of its transport in intestinal cells. This mechanism is unique because it bypasses membrane vesicles (vesicles) and may form the basis of a new therapy.Cholesterol is a fat-like compound that is found in large amounts in the membranes of animal and human cells. It is necessary for their normal operation, but in excess causes atherosclerosis and increases the risk of cardiovascular disease. Those, in turn, take millions of lives worldwide every year.
Therefore, it is necessary to get rid of excess circulating cholesterol in the blood, for which pharmacological drugs are used. However, the mechanisms by which they work are not yet fully known. In addition, it is always useful to have alternative approaches to treatment and to supplement their arsenal. This requires a detailed understanding of cholesterol metabolism in norm and pathology. Until recently, there has been a large gap, which has just been filled by a publication in Science.
In the human body, cholesterol either comes from outside with food or is synthesized in the liver. In the first case, its absorption occurs in the small intestine, where cholesterol is taken up by the microvilli of the lining cells - enterocytes - covering the finger-like outgrowths of the intestinal mucosa. From their outer membranes, cholesterol enters the endoplasmic reticulum (EPR), a large organelle responsible for synthesis and transport of substances in the cell. It was this stage that remained a "white spot": scientists had to find out how cholesterol is transported inside enterocytes to their ESR.
By the way, after that cholesterol in enterocytes is packed into particles that also contain specific proteins - chylomicrons. Those enter the blood and deliver cholesterol throughout the body.
The authors of the new work used a number of methods: transgenic models in mice, the study of the structure of biomolecules and the creation of enteroids. These are cultured intestinal cells of different types, which grow together and therefore well reproduce the work of a real organ.
It turned out that cholesterol transport in enterocytes does not depend on membrane vesicles - the main way of "cargo delivery" in the cell. Instead, the two large membranes of the enterocyte - the outer (cytoplasmic) and EPR membrane - directly contact, due to which cholesterol gets into the reticulum.
The process is provided by two proteins, NPC1L1 and Aster, which work in sequence. The researchers took into account that disrupting the transfer of cholesterol with their help means avoiding its excess into the blood. The scientists successfully inhibited the activity of the second protein (Aster) and thus prevented hypercholesterolemia (high concentration of cholesterol in the blood) in mice that received large amounts of this lipid with food.
The new result is significant because it can be used to reduce cholesterol in human blood. This could prevent many of its dangerous effects that now threaten millions of people.