BIOCHEMISTRY - Textbook - Ostapchenko L. I. - 2012

Chapter 14. LIPID METABOLISM

14.8. Cholesterol Synthesis

Cholesterol synthesis is one of the most complex biosynthetic pathways in animal Tissues. It occurs primarily in the Liver, as well as in several other tissues, and can be outlined as shown in Fig. 14.11.

As seen from the scheme, this intricate process is conventionally divided into five stages. In The First stage, three molecules of acetyl-CoA undergo Condensation (mediated by thiolase and synthase) to form a molecule of 3-hydroxy-3-methylglutaryl-CoA, which is then reduced by 3-hydroxy-3-methylglutaryl-CoA reductase into mevalonic acid. In the second stage, mevalonate is phosphorylated three times by mevalonate kinase to yield 3-phospho-5-diphosphomevalonate. The latter is rapidly dephosphorylated and decarboxylated, converting into 3-isopentenyl diphosphate, the activated form of isoprene. In the Third Stage, six molecules of 3-isopentenyl diphosphate combine to form the 30-carbon linear molecule squalene. In the Fourth Stage, squalene is converted first into squalene oxide in the presence of O₂ and NADPH, and then cyclized into lanosterol. In The final stage of synthesis, lanosterol is demethylated by losing three methyl groups, one of its two double bonds is reduced, and it is ultimately converted into cholesterol.

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Fig. 14.11. Scheme of cholesterol synthesis

Cholesterol synthesis is primarily regulated by a feedback inhibition mechanism mediated by mevalonate and cholesterol itself. As the end product, cholesterol inhibits the entire synthesis process at an early stage by suppressing the key regulatory enzyme of the biosynthetic pathway—hydroxymethylglutaryl-CoA reductase.

The enzyme's activity is also regulated by dietary cholesterol: exogenous cholesterol suppresses the synthesis of endogenous cholesterol by inhibiting hydroxymethylglutaryl-CoA reductase. Additionally, The activity of this enzyme is controlled by Hormones. Glucagon, via the intracellular messenger cAMP and with the involvement of phosphoprotein kinase, phosphorylates the reductase, converting it into an inactive form. Insulin, conversely, promotes the dephosphorylation of the enzyme through The stimulation of phosphatase, thereby converting it into its active form.

Impairments in the endocrine control of steroidogenesis—for instance, caused by excessive intake of carbohydrate- and fat-rich foods, which stimulates insulin-driven cholesterol synthesis—represent a significant risk factor for The Development of atherosclerosis.