Transport of dietary cholesterol and the role of chylomicrons
Although absolutely all types of lipoprotein take part in lipid transport, at the very first stage—the stage of absorption of exogenous (dietary) cholesterol—chylomicrons (CM) play the leading role. This process originates in the intestinal cells known as enterocytes.
Inside chylomicrons, cholesterol exists in two main forms:
- Free cholesterol.
- Cholesterol esters. For their formation in the intestinal mucosa, a specialized enzyme operates — acyl-CoA:cholesterol acyltransferase (abbreviated as ACAT).
As soon as mature chylomicrons leave the intestinal cells and enter the bloodstream, their active metabolism begins. In the blood, they are acted upon by the enzyme lipoprotein lipase (LPL). Its key task is to hydrolyze fats (triacylglycerols) that are part of chylomicrons. As a result of this enzymatic cleavage, chylomicrons "slim down" and turn into so-called remnant chylomicrons. These remnant particles, still containing a significant amount of cholesterol, are ultimately captured by liver cells — hepatocytes.
Familial hypercholesterolemia (Type II)
Among all lipid metabolism disorders accompanied by elevated cholesterol levels, familial hypercholesterolemia is the most common disease. This is a classic example of hyperlipoproteinemia with a clear genetic nature.
Epidemiology and genetics: Heterozygous carriers of the defective gene occur in the population at a frequency of 1 in 500 individuals. The etiology of the disease itself lies in various mutations affecting the gene encoding the LDL (low-density lipoprotein) receptor protein. This gene features a highly complex structure including numerous introns and exons, which accounts for a huge number of possible disruptions: to date, over 300 types of various mutations have been described.
The pathogenesis of the disease develops through the following chain:
- The presence of a genetic mutation leads to damage in the normal structure of the LDL receptor.
- The defective receptor loses the ability to carry out endocytosis after binding to LDL.
- Due to the blockage of lipoprotein entry into cells, blood cholesterol levels rise rapidly, and hypercholesterolemia develops.
- Chronic plasma cholesterol excess inevitably leads to the formation of early atherosclerosis.
Biochemical foundations of atherosclerosis development
A natural and most formidable outcome of long-standing dyslipoproteinemia (in particular, familial hypercholesterolemia type II) is atherosclerosis.
From a biochemical and pathophysiological standpoint, atherosclerosis is a disease characterized by specific damage to the inner layer of the arterial wall. The key link in this process is the pathological deposition of excess cholesterol in the vascular intima. It is the intima (the inner lining) that becomes the target for lipid infiltration, which subsequently leads to vessel lumen narrowing, impaired blood flow, and the development of severe ischemic complications.
Briefly: answers to topical questions
What types of hyperlipoproteinemia exist according to the Fredrickson classification?
The provided sources describe the following types of hyperlipoproteinemia (Fredrickson's name itself is not mentioned):
- Type II — familial hypercholesterolemia. Characterized by elevated LDL concentration and the development of hypercholesterolemia due to mutations in the LDL receptor gene or apoB-100.
- Type III — familial combined hyperlipidemia. Manifests as elevated concentrations of remnant CM, VLDL, IDL, and LDL due to a defect in the apoE structure.
- Types IV and V — familial hypertriacylglycerolemia. Caused by overproduction of VLDL, leading to hypertriacylglycerolemia.
Which lipoproteins are responsible for the reverse transport of cholesterol from tissues to the liver?
High-density lipoproteins (HDL) are responsible for reverse cholesterol transport. They perform the function of removing excess free cholesterol from peripheral tissues, including vascular walls and macrophages, and transport it to the liver. In the liver, cholesterol is converted into bile acids or excreted with bile. Due to this, HDL reduce cholesterol accumulation in the vascular wall and prevent the development of atherosclerosis, meaning they are antiatherogenic.
What role does the LCAT enzyme play in lipoprotein metabolism?
The enzyme lecithin-cholesterol acyltransferase (LCAT) is responsible for the esterification of free cholesterol on the surface of high-density lipoproteins (HDL). Its action leads to the following results:
- The resulting hydrophobic cholesterol esters embed into the center (core) of the HDL particle.
- Discoid (immature) HDL acquire a spherical shape, increase in size, and turn into HDL₃.
- A concentration gradient is created, allowing HDL to capture new portions of cholesterol from vascular wall macrophages and other peripheral tissues.
Thus, LCAT accelerates reverse cholesterol transport to the liver and reduces the risk of atherosclerosis.
To remember where exactly cholesterol is deposited in atherosclerosis, use the mnemonic: cholesterol seeks an "INTIMATE" relationship with the vessel, so it accumulates in the inner layer — the intima.
Class and exam questions
What happens to chylomicrons after they enter the blood?
In the bloodstream, they are acted upon by lipoprotein lipase, which hydrolyzes the fats (TAG) contained within them. Thereafter, remnant chylomicrons are formed, which are captured by hepatocytes.
Which enzyme is responsible for the formation of cholesterol esters in the intestine?
This process is catalyzed by the enzyme ACAT (acyl-CoA:cholesterol acyltransferase), which operates in the cells of the intestinal mucosa.
What is the pathogenesis of familial hypercholesterolemia type II?
Mutations disrupt the structure of the LDL receptor, preventing it from performing endocytosis. This leads to cholesterol accumulation in the blood and the development of early atherosclerosis.
What else to study on this topic
- Transport of endogenous cholesterol in the body
- Mechanisms of reverse cholesterol transport
- Full classification of hyperlipoproteinemias
- Structural organization of the LDL receptor gene (exons and introns)
- Detailed stages of atherosclerotic plaque formation in the intima
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