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Cholesterol Metabolism

Cholesterolum

For medical students2 min readUpdated 2026-10-10

Cholesterol is a crucial steroid in the body essential for cell membrane structure, bile acid synthesis, steroid hormone production, and vitamin D₃ synthesis. Its metabolism involves dietary intake, tissue synthesis (predominantly in the liver), and strict regulation of the rate-limiting enzyme HMG-CoA reductase.

SynthesisUp to 1 g/day is synthesized de novo from acetyl-CoA.

Localization75–80% is synthesized in the liver, 15% in the small intestine.

Normal LevelBlood concentration is typically less than 5.2 mmol/L (200 mg/dL).

StructureA complex polycyclic cyclopentanoperhydrophenanthrene structure with an OH group at C3.

Biological Role and Distribution

Cholesterol performs three main functions in the body:

Structural: A component of cell membranes, regulating the fluidity of the hydrophobic bilayer.
Transport: Combines with phospholipids to form the surface monolayer of lipoproteins.
Metabolic: Serves as a precursor for bile acids, steroid hormones, and vitamin D₃.

The body contains approximately 140 g of cholesterol, with the vast majority (93%) located intracellularly. The pool is constantly replenished by endogenous synthesis (~1 g/day) and exogenous dietary intake (0.3–0.5 g/day). 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 fat contains mostly cholesterol esters. In the intestinal lumen, pancreatic cholesterol esterase hydrolyzes them into free cholesterol and fatty acids.

These digestion products are absorbed in mixed micelles. Within enterocytes, re-esterification occurs: ACAT (acyl-CoA:cholesterol acyltransferase) transfers an acyl group from acyl-CoA to the hydroxyl group of cholesterol, forming new cholesterol esters. These esters are then packaged into chylomicrons for transport via the lymphatic system into the bloodstream. 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 nucleated cells, predominantly in the liver. The process is most active during the postprandial (absorptive) state.

The source of all 27 carbon atoms is acetyl-CoA, and the reducing equivalents come from NADPH. The pathway involves about 30 reactions. Key steps include:

Formation of mevalonate: Acetyl-CoA molecules are converted to HMG-CoA. Then, catalyzed by HMG-CoA reductase (consuming NADPH), it is reduced to mevalonate. This is the rate-limiting step of the entire pathway.
Formation of squalene: Mevalonate molecules are phosphorylated (consuming ATP) and condensed to form the 30-carbon linear hydrocarbon squalene.

Regulation of Synthesis

The primary control point is the enzyme HMG-CoA reductase. Its activity is regulated through several mechanisms:

Covalent modification: Insulin promotes dephosphorylation of the enzyme, converting it into its active form. Glucagon, conversely, stimulates phosphorylation (via a kinase cascade), inactivating the enzyme. Thus, synthesis is promoted during the fed state and suppressed during fasting.
Changes in enzyme quantity: Intracellular cholesterol and bile acids suppress transcription of the enzyme's gene and accelerate its proteolytic degradation. Estrogens, conversely, stimulate gene expression.
Allosteric regulation: Excess end products can also affect enzyme activity.

Frequently asked questions

What are the main stages of cholesterol biosynthesis?

The main stages of cholesterol biosynthesis are mevalonate formation, squalene synthesis, and its conversion to cholesterol.

Stage I — Formation of mevalonate from acetyl-CoA molecules in the cytosol. This is the regulatory, rate-limiting step catalyzed by HMG-CoA reductase.
Stage II — Formation of squalene. Condensation of phosphorylated isoprenoid intermediates to form a 30-carbon linear compound.
Stage III — Conversion of squalene to cholesterol. This includes cyclization to form the intermediate lanosterol followed by subsequent modifications involving the loss of three carbon atoms.

Which lipoproteins are responsible for the reverse cholesterol transport from peripheral tissues to the liver?

High-density lipoproteins (HDL) are responsible for reverse cholesterol transport from peripheral tissues and the bloodstream back to the liver.

These lipoproteins perform an "anti-atherogenic" function. They capture free cholesterol from peripheral cell membranes, esterify it within their particle core (via the LCAT enzyme), and deliver it to the liver. In the liver, cholesterol is taken up for elimination, conversion into bile acids, or excretion, thereby reducing lipid 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 — 3α,7α,12α-trihydroxy-5β-cholanoic acid.
Chenodeoxycholic acid — 3α,7α-dihydroxy-5β-cholanoic acid.

Following hepatic synthesis, primary bile acids are conjugated with glycine or taurine and secreted into bile.

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. Dephosphorylation is stimulated by insulin.

Where do the carbon atoms for cholesterol synthesis come from?

All 27 carbon atoms of cholesterol are derived from acetyl-CoA.

Go deeper

Conversion stages of squalene to cholesterol
Lipoprotein metabolism (Chylomicrons, VLDL, LDL, HDL)
Bile acid synthesis from cholesterol
Steroid hormone synthesis
Vitamin D₃ synthesis