Forms in the body
Cholesterol is present in tissues and plasma in two main forms:
- Free (unesterified) cholesterol is a structural component of biological membranes. In plasma membranes, it is located in the outer layer, with its ratio to phospholipids being approximately 1:1. The free form is also present on the surface of lipoprotein particles.
- Cholesterol esters are the storage form. It is in the form of esters that cholesterol accumulates in cells synthesizing steroid hormones and is transported in the internal hydrophobic core of lipoproteins.
Forward transport (from liver to tissues)
Transport of endogenous cholesterol is mediated by very-low-density and low-density lipoproteins (VLDL and LDL).
- The liver synthesizes the protein component apoB-100 and assembles immature VLDL.
- In the bloodstream, they acquire apolipoproteins E and CII from high-density lipoproteins (HDL), becoming mature particles.
- Under the action of lipoprotein lipase on the capillary endothelium (activated by apoC-II), VLDL lose triacylglycerols and are converted into intermediate-density lipoproteins (IDL).
- They subsequently convert into LDL, which interact with peripheral tissue or liver receptors via the apoB-100 protein, delivering cholesterol to cells.
Reverse transport (to the liver)
Excess cholesterol from peripheral tissues must be removed. This task is accomplished by HDL, which are synthesized in the liver and small intestine as disc-shaped precursors. In their immature state, they are rich in phospholipids and contain apolipoproteins E, C-II, A-I, and A-II, but have almost no cholesterol.
The process of cholesterol uptake and packaging occurs in several stages:
- The cellular protein ABC1 transfers cholesterol from the cell membrane to the HDL particle (contact is mediated by apoA-I or apoE).
- On the HDL surface, the enzyme lecithin-cholesterol acyltransferase (LCAT) is activated. Its activator is the apoA-I protein.
- LCAT catalyzes the esterification reaction: a fatty acid is transferred from phosphatidylcholine to cholesterol. Hydrophobic cholesterol esters are formed.
- The esters move into the core of the particle. As a result, HDL acquire a spherical shape, increase in size, and turn into HDL₃.
Then HDL deliver cholesterol to the liver, where it is partially converted into bile acids and excreted in feces.
Briefly: answers to topical questions
Which receptors mediate cellular uptake of LDL and how does this process occur?
Cellular uptake of LDL is mediated by specific LDL receptors via endocytosis.
The process proceeds as follows:
- Cell receptors recognize apolipoproteins on the LDL surface (specifically, apoB-100 and apoE).
- Following the interaction between the receptor and the lipoprotein, the complex undergoes endocytosis into the cell.
- Genetic mutations of the receptor impair the ability to undergo endocytosis after interacting with LDL, leading to the development of hypercholesterolemia.
Through what pathways is cholesterol eliminated from the body?
The primary route of cholesterol elimination from the body is via the intestine with feces.
Excess cholesterol in the liver is eliminated by the following mechanisms:
- In the form of synthesized bile acids (~0.5 g per day).
- In unchanged form (~0.5 g per day).
A total of 1.0–1.3 g/day is eliminated through the intestine, which accounts for more than 90% of all excreted cholesterol. This pathway is the main mechanism for maintaining steroid homeostasis. Only a minor amount is eliminated via other pathways.
What key enzyme regulates endogenous cholesterol synthesis in the liver?
Endogenous cholesterol synthesis is regulated by the key enzyme HMG-CoA reductase (3-hydroxy-3-methylglutaryl-CoA reductase).
Enzyme activity is regulated through the following mechanisms:
- Activation — occurs with increased insulin secretion (stimulates enzyme dephosphorylation) and under the action of phosphatases.
- Inactivation — is caused by the action of kinases (phosphorylation is stimulated by glucagon), decreased glucose concentration during fasting, and excessive dietary cholesterol intake (allosteric inhibition).
Excess cholesterol suppresses the expression of HMG-CoA reductase via feedback inhibition.
Class and exam questions
Why does cholesterol freely circulate in the blood if it is insoluble in water?
In plasma, cholesterol does not exist in a free state; rather, it is packaged into the hydrophobic core of lipoprotein complexes, which ensure its solubility and transport.
What is the difference between free cholesterol and its esters?
Free cholesterol is a component of membranes and lipoprotein shells, whereas esters represent the hydrophobic form for cellular storage and transport within the lipoprotein core.
Which foods are sources of cholesterol?
Cholesterol is found exclusively in animal products: meat, liver, brain, egg yolks, and cheese. Plant sterols are practically unabsorbed in the intestine.
What else to study on this topic
- Mechanism of intestinal cholesterol absorption (the role of mixed micelles)
- Synthesis and structure of apolipoproteins (apoB-100, apoA-I, apoE)
- Action of lipoprotein lipase on vascular endothelium
- Conversion of cholesterol into bile acids in the liver
- Interaction of LDL with cellular receptors
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