Biological role and distribution
Cholesterol performs three main functions in the body:
- Structural: a component of cell membranes, regulating the fluidity of the hydrophobic layer.
- Transport: forms the surface layer of lipoproteins together with phospholipids.
- Metabolic: serves as a precursor for the synthesis of bile acids, steroid hormones, and vitamin D₃.
The human body contains about 140 g of cholesterol, with the vast majority (93%) located intracellularly. The pool is continuously replenished through endogenous synthesis (about 1 g per day) and dietary intake (0.3–0.5 g). Cholesterol is primarily consumed in the formation of bile acids (0.5–0.7 g/day) and is also excreted via feces and sebum.
Digestion and transport
Dietary intake consists mainly of cholesterol esters. In the intestine, they are cleaved by pancreatic cholesterol esterase into free cholesterol and fatty acids.
The cleavage products are absorbed as mixed micelles. Resynthesis takes place within the intestinal mucosal cells (enterocytes): the enzyme ACAT (acyl-CoA cholesterol acyltransferase) transfers an acyl residue from acyl-CoA to the hydroxyl group of cholesterol, forming new esters. These esters are then packaged into chylomicrons for transport into the lymphatic system and subsequently into the blood. Remnant chylomicrons are taken up by the liver via apoE receptors.
De novo biosynthesis
Cholesterol synthesis occurs in the cytosol and endoplasmic reticulum of most cells, but predominantly in the liver. The process is most active in the postprandial period (absorptive state).
Acetyl-CoA serves as the source for all 27 carbon atoms, and NADPH provides the hydrogen. The pathway involves about 30 reactions. Key stages:
- Formation of mevalonate: HMG-CoA is synthesized from acetyl-CoA molecules. Then, driven by HMG-CoA reductase (consuming NADPH), it is reduced to mevalonate. This is the rate-limiting reaction of the entire pathway.
- Formation of squalene: mevalonate molecules are phosphorylated (consuming ATP) and condensed to form the 30-carbon linear squalene.
Regulation of synthesis
The main control point is the enzyme HMG-CoA reductase. Its activity is regulated in several ways:
- Covalent modification: Insulin promotes dephosphorylation of the enzyme, converting it to its active form. Glucagon, conversely, stimulates phosphorylation (via kinase), inactivating the enzyme. Thus, synthesis proceeds during satiety and is inhibited during fasting.
- Change in enzyme quantity: Cholesterol and bile acids suppress transcription of the enzyme gene and accelerate its proteolysis. Estrogens, conversely, stimulate gene expression.
- Allosteric regulation: excess end products also affect enzyme activity.
Briefly: answers to topical questions
What are the main stages of cholesterol biosynthesis?
The main stages of cholesterol biosynthesis are the formation of mevalonate, the synthesis of squalene, and its conversion into cholesterol.
- Stage I — Formation of mevalonate from acetyl-CoA molecules in the cytosol. This is the regulatory step catalyzed by HMG-CoA reductase.
- Stage II — Formation of squalene. Phosphorylated isoprenoid derivatives condense to form a 30-carbon linear compound.
- Stage III — Conversion of squalene into cholesterol. This includes cyclization to form the intermediate product lanosterol followed by subsequent modifications involving the loss of three carbon atoms.
Which lipoproteins are responsible for the reverse transport of cholesterol from peripheral tissues to the liver?
High-density lipoproteins (HDL) are responsible for the reverse transport of cholesterol from peripheral tissues and blood to the liver.
These lipoproteins perform an "antiatherogenic" function. They capture free cholesterol from the membranes of peripheral cells, esterify it within their particle (via the LCAT enzyme), and deliver it to the liver. In the liver, cholesterol is taken up for further utilization, conversion into bile acids, or excretion, which reduces its accumulation in the vascular wall.
Which specific bile acids are synthesized from cholesterol in the liver?
In the liver, cholesterol is consumed in the synthesis of primary bile acids.
These include:
- Cholic acid — 3,7,12-trihydroxycholanic acid.
- Chenodeoxycholic acid — 3,7-dihydroxycholanic acid.
Following hepatic synthesis, primary bile acids are conjugated with glycine or taurine and secreted into bile.
Class and exam questions
Which enzyme limits the rate of cholesterol synthesis?
The key regulatory enzyme is HMG-CoA reductase, which converts HMG-CoA into mevalonate.
In what state is HMG-CoA reductase active?
In the dephosphorylated state. The dephosphorylation process is stimulated by insulin.
Where do the carbon atoms for cholesterol synthesis come from?
All 27 carbon atoms of cholesterol originate from acetyl-CoA.
What else to study on this topic
- Stages of squalene conversion to cholesterol
- Lipoprotein metabolism (CM, VLDL, LDL, HDL)
- Synthesis of bile acids from cholesterol
- Synthesis of steroid hormones
- Formation of vitamin D₃
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