Cholesterol is an essential sterol that modulates membrane fluidity and serves as a precursor for bile acids, steroid hormones, and vitamin D. Its metabolism is tightly regulated to maintain cellular cholesterol homeostasis, as both excess and deficiency can have serious consequences.
Cholesterol Structure
Cholesterol consists of a tetracyclic cyclopentanoperhydrophenanthrene ring system with a hydroxyl group at position 3, a double bond between carbons 5 and 6, and an eight-carbon isooctyl side chain at position 17. The hydroxyl group makes cholesterol amphipathic, orienting it in membranes with the hydroxyl group at the aqueous interface.
Cholesterol Biosynthesis
Cholesterol synthesis occurs primarily in the liver and begins with acetyl-CoA, a central metabolite in fatty acid oxidation and synthesis. The pathway involves four stages. First, three molecules of acetyl-CoA are condensed to form mevalonate through the action of HMG-CoA synthase and HMG-CoA reductase. HMG-CoA reductase catalyzes the rate-limiting step and is the target of statin drugs. Second, mevalonate is converted to the activated isoprene units isopentenyl pyrophosphate and dimethylallyl pyrophosphate. Third, six isoprene units condense to form squalene, a 30-carbon linear molecule. Fourth, squalene cyclizes to form the steroid ring structure, which is further modified through several steps to yield cholesterol.
Regulation of Cholesterol Synthesis
Cholesterol synthesis is regulated primarily at the level of HMG-CoA reductase activity, through multiple mechanisms. High cholesterol levels decrease transcription of the HMG-CoA reductase gene by reducing the nuclear levels of SREBP transcription factors. Cholesterol also promotes the degradation of HMG-CoA reductase protein and inhibits its activity through phosphorylation. Insulin upregulates cholesterol synthesis, while glucagon inhibits it.
Bile Acid Synthesis
The liver converts cholesterol into bile acids, the major route of cholesterol elimination from the body. The rate-limiting enzyme is cholesterol 7-alpha-hydroxylase, which adds a hydroxyl group to the steroid ring. Bile acids are conjugated with glycine or taurine to form bile salts, which are secreted into bile and stored in the gallbladder. Bile salts emulsify dietary fats in the small intestine, facilitating their digestion and absorption.
Steroid Hormone Synthesis
Cholesterol is the precursor for all steroid hormones. Pregnenolone is formed by side-chain cleavage and serves as the parent compound for all other steroid hormones. These include mineralocorticoids such as aldosterone, which regulate salt and water balance, glucocorticoids such as cortisol, which regulate metabolism and immune function, and sex hormones including androgens, estrogens, and progestins.
Vitamin D Synthesis
7-Dehydrocholesterol, a derivative of cholesterol, is converted to cholecalciferol in the skin upon exposure to ultraviolet light. Cholecalciferol is then hydroxylated in the liver to 25-hydroxycholecalciferol and in the kidney to the active form, 1,25-dihydroxycholecalciferol, which regulates calcium and phosphate metabolism.
Disorders of Cholesterol Metabolism
Familial hypercholesterolemia results from mutations in the LDL receptor, leading to elevated blood cholesterol and premature atherosclerosis. Sitosterolemia is a rare disorder of increased intestinal absorption and decreased biliary excretion of plant sterols and cholesterol. Smith-Lemli-Opitz syndrome is caused by a defect in 7-dehydrocholesterol reductase, resulting in reduced cholesterol synthesis and multiple developmental abnormalities.
