Main classes of lipoproteins
Lipoprotein particles differ in density, size, and composition:
- VLDL (Very Low-Density Lipoproteins): Transport endogenous fats from the liver primarily to adipose tissue. They have a size of 30–100 nm and a density of 0.96–1.00 g/mL. The main lipid component is triacylglycerols (TAG), making up about 50–55% of the mass. The main protein is apoB-100.
- LDL (Low-Density Lipoproteins): Formed in the bloodstream during lipolysis. About 50% of their composition consists of cholesterol and its esters.
- HDL (High-Density Lipoproteins): Responsible for "scavenging" excess cholesterol from cell membranes and other blood lipoproteins, and also act as donors of apolipoproteins.
- Chylomicrons (CM): Formed in the intestine, they transport exogenous (dietary) fats. Their marker protein is apoB-48.
Formation and maturation of VLDL
VLDL synthesis occurs in hepatocytes. A common cholesterol pool is formed in the liver, including both exogenous (from food) and endogenous (synthesized by the liver itself) cholesterol.
Together with TAG, this cholesterol is packaged into immature VLDL. A special microsomal triglyceride transfer protein plays a crucial role in this process by transporting TAG into the lipoprotein particle. The apoB-100 protein serves as the structural backbone.
Upon entering the bloodstream, immature particles encounter HDL, from which they receive apoE and apoC-II proteins. Only after this do VLDL become mature and able to fully perform their functions.
HDL metabolism and cholesterol ester transport
HDL are synthesized in the liver and intestine as immature (discoidal) particles. Immediately upon entering the blood, they act as donors of apoC-II and apoE for CM and VLDL.
Next, the "scavenging" function begins: HDL pick up excess cholesterol. The enzyme lecithin-cholesterol acyltransferase (LCAT), activated by the apoA-I protein, operates on their surface. LCAT converts free cholesterol into esters (CE) and sequesters them inside the particle.
As cholesterol esters accumulate, the discoidal particle turns into spherical HDL₃, and with further saturation — into larger HDL₂. Then cholesterol ester transfer protein (CETP) comes into play: it transfers CE from HDL to LDL or VLDL in exchange for TAG.
At the end of the cycle, on the surface of hepatocytes, hepatic lipase hydrolyzes TAG inside HDL₂, reducing their size and converting them back into HDL₃.
Mechanisms of cholesterol return to the liver
The collected cholesterol esters return to hepatocytes via three pathways:
- Endocytosis via LDL receptors (main pathway). Liver receptors recognize apoB-100 and apoE proteins located on the surface of remnant chylomicrons, IDL, and LDL.
- Via scavenger receptors (SR-B1). This pathway ensures the direct transfer of cholesterol esters from HDL to hepatocytes, especially after the action of hepatic lipase.
- HDL endocytosis (minor pathway). A small fraction of HDL is taken up by cells entirely through the interaction of their apoE with corresponding receptors.
Lipoprotein lipase (LPL) isoforms
The LPL enzyme, which breaks down fats within lipoproteins, has different isoforms in tissues that differ in substrate affinity—the Michaelis constant ($K_m$):
- In adipose tissue, $K_m$ is high (affinity is low). The enzyme is active only in the absorptive state when blood lipoprotein concentrations are high. Its purpose is energy storage during food abundance.
- In muscle tissue, $K_m$ is low (affinity is high). Muscles can efficiently utilize fatty acids even at low concentrations, which is necessary for a constant energy supply during muscle work.
Briefly: answers to topical questions
What are the functions of apolipoprotein apoC-II?
Apolipoprotein apoC-II acts as an activator of lipoprotein lipase.
- Enzyme activation — lipoprotein lipase "recognizes" chylomicrons through interaction with apoC-II; after this, the enzyme hydrolyzes TAG within chylomicrons into glycerol and free fatty acids.
- Lipoprotein maturation — apoC-II is transferred from HDL to immature chylomicrons and VLDL, thereby maturing them.
A structural defect in apoC-II is noted as a genetic defect in hereditary type I hyperchylomicronemia; this results in elevated blood chylomicrons and VLDL, and accumulated TAG.
What happens when LDL receptors are defective?
When LDL receptors are defective, the uptake of low-density lipoproteins by tissues is impaired due to the loss of receptor-mediated endocytosis capability.
As a result of these disturbances, the following changes occur:
- Lipid accumulation — due to LDL receptor deficiency, both LDL and cholesterol accumulate in blood plasma, while endogenous cholesterol synthesis in the liver is not inhibited.
- Disease development — primary familial hypercholesterolemia (type IIa) develops.
- Clinical manifestations — the disease is accompanied by pronounced premature coronary atherosclerosis and xanthomatosis.
Class and exam questions
Why do VLDL contain apoB-100 and chylomicrons contain apoB-48 if the gene is the same?
This is due to post-transcriptional modifications (RNA editing). 100% of the coding part of the gene is read in the liver, producing apoB-100. In intestinal cells, only 48% is read, yielding the truncated apoB-48 protein.
How do immature VLDL mature?
In the bloodstream, they encounter HDL, which donate their apoE and apoC-II proteins to them. Having received these apolipoproteins, VLDL turn into mature particles capable of interacting with enzymes and receptors.
What is the role of CETP?
It mediates lipid exchange between lipoproteins: it extracts cholesterol esters from HDL and transfers them to VLDL and LDL, receiving triacylglycerols (TAG) in return.
What else to study on this topic
- Structure and regulation of lecithin-cholesterol acyltransferase (LCAT)
- Molecular mechanism of microsomal triglyceride transfer protein (MTP) action
- Interaction of scavenger receptors (SR-B1) with HDL on the hepatocyte surface
- Comparison of hepatic, pancreatic, and hormone-sensitive lipases
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