Biological functions of cholesterol
Cholesterol is an animal sterol that performs several key functions in the body:
- a structural component of biological membranes, regulating the viscosity of the hydrophobic layer;
- a component of the lipoprotein monolayer and their hydrophobic core (in the form of esters);
- a precursor in the synthesis of bile acids, steroid hormones, and vitamin D3.
The cholesterol molecule is based on a cyclopentanoperhydrophenanthrene nucleus, containing a hydroxyl group at C3, a double bond between C5 and C6, and a side hydrocarbon chain. Despite the presence of the OH group, the compound is poorly soluble in water.
Ingestion and digestion
Cholesterol enters the body with animal foods (meat, liver, brain, egg yolk, cheese). Plant sterols are practically not absorbed in the intestine. Endogenous synthesis amounts to 0.5–1 g/day and depends on the amount of dietary cholesterol.
In the intestine, dietary cholesterol esters are hydrolyzed by the enzyme cholesterol esterase to form free cholesterol and a fatty acid. Hydrolysis products are absorbed by the epithelium as part of mixed micelles. In enterocytes, cholesterol is re-esterified with the participation of acyl-CoA:cholesterol acyltransferase (ACAT): the reaction involves the activation of a fatty acid and the transfer of the acyl residue to the OH group of cholesterol. Cholesterol esters are incorporated into chylomicrons and enter the lymph, and then the blood.
Cholesterol biosynthesis
Synthesis occurs in the liver (the main organ), small intestine, skin, adrenal cortex, and gonads. The initial substrate is acetyl-CoA, formed during glycolysis. The process is energy-consuming, occurs during the absorptive period, and requires NADPH (sourced from the pentose phosphate pathway) and ATP.
Synthesis is divided into three stages:
- Formation of mevalonate. Two molecules of acetyl-CoA are condensed by thiolase into acetoacetyl-CoA; HMG-CoA synthase adds a third acetyl-CoA to form β-hydroxy-β-methylglutaryl-CoA (HMG-CoA). The regulatory enzyme HMG-CoA reductase reduces HMG-CoA to mevalonate using 2 NADPH.
- Formation of squalene. Mevalonate is phosphorylated (3 ATP per molecule) and decarboxylated to isopentenyl pyrophosphate; condensation of six such molecules yields squalene.
- Cyclization. Squalene in the endoplasmic reticulum with the participation of microsomal oxidation enzymes is converted into lanosterol, and then into cholesterol.
Regulation of HMG-CoA reductase
The key regulatory enzyme is HMG-CoA reductase. Regulation is carried out at several levels:
- Transcriptional control. Cholesterol and its oxyderivatives (25-hydroxycholesterol, 24,25-epoxycholesterol), as well as bile acids, act as corepressors of enzyme mRNA synthesis. Estrogens induce its expression.
- Proteolytic degradation. Excess cholesterol and bile acids accelerate the proteolysis of the enzyme.
- Covalent modification. Insulin, through the activation of phosphatase, causes dephosphorylation and activation of the reductase. Glucagon and steroid hormones lead to phosphorylation and inactivation.
- Energy control. When AMP increases, AMP-activated protein kinase is activated, which phosphorylates and inactivates the enzyme.
Competitive inhibitors of HMG-CoA reductase are statins, the main class of drugs for the correction of hypercholesterolemia.
Cholesterol Transport: LDL
Low-density lipoproteins (LDLs) are formed in the bloodstream from VLDLs and transport cholesterol to peripheral tissues. Cellular uptake occurs via receptor-mediated endocytosis through LDL receptors, which recognize apoB-100 and apoE apoproteins. These same receptors capture remnant chylomicrons and VLDLs.
Prolonged elevation of plasma LDLs promotes cholesterol deposition in vessel walls and the development of atherosclerosis; therefore, LDLs are clinically referred to as "bad" cholesterol.
Reverse Cholesterol Transport: HDL
High-density lipoproteins (HDLs) are synthesized in the liver and small intestine as a disk-shaped precursor poor in cholesterol, but rich in phospholipids and apoA1, apoA2, apoC, apoE apoproteins. In the blood, HDLs transfer apoC and apoE to chylomicrons and VLDLs, and then extract excess cholesterol from cell membranes.
The esterification of collected cholesterol is catalyzed by the enzyme LCAT (lecithin-cholesterol acyltransferase), activated by apoA1:
cholesterol + phosphatidylcholine → cholesterol ester + lysophosphatidylcholine
Hydrophobic esters are embedded into the particle core, and HDL acquire a spherical shape (HDL3). Cholesterol esters are transferred to VLDL and LDL via cholesteryl ester transfer protein (CETP) in exchange for triacylglycerols. As TAG accumulate, HDL3 convert into HDL2; hepatic lipase hydrolyzes TAG, returning the particles to the HDL3 form.
The uptake of cholesterol esters into hepatocytes occurs via scavenger receptors SR-B1, as well as through LDL receptors and, to a lesser extent, via endocytosis of whole HDLs. By removing excess cholesterol, HDLs exert an antiatherogenic effect and are referred to as "good" cholesterol.
Fate of Cholesterol in the Liver
In hepatocytes, cholesterol is primarily converted into bile acids and excreted with bile. A portion is excreted unchanged or in esterified form; a small amount is eliminated via sebum. The final balance between intake, synthesis, excretion, and distribution between LDL and HDL determines the total plasma cholesterol level and the risk of atherosclerosis.
Key points
- HMG-CoA reductase is the key regulatory enzyme of cholesterol synthesis and the target of statins.
- Cholesterol synthesis proceeds from acetyl-CoA, requires NADPH and ATP, and is active during the absorptive state.
- Regulation of reductase: repression by cholesterol and bile acids, induction by estrogens, activation by insulin, and inactivation by glucagon and AMP-activated protein kinase.
- LDLs deliver cholesterol to tissues via LDL receptors (recognizing apoB-100 and apoE); their excess is atherogenic.
- HDLs perform reverse cholesterol transport to the liver and exhibit an antiatherogenic effect.
- Cholesterol esterification in plasma is catalyzed by LCAT, activated by apoA1.
- The transfer of cholesterol esters between lipoproteins is mediated by CETP.
- The primary pathway of cholesterol elimination is conversion into bile acids in the liver.