0.5. Note where cholesterol is synthesized. (added for my own benefit)
Cholesterol is synthesized by virtually all tissues in humans, but liver, intestine, adrenal cortex, and reproductive tissues (including ovaries, testes, and placenta) make the largest contributions.
1. Follow the major steps in the synthesis of cholesterol and list the key intermediates.
Acetoacetyl CoA + Acetyl CoA → 3-hydroxy-2-methylglutaryl (HMG) CoA (via HMG-CoA synthase)
HMG CoA + 2 NADPH → Mevalonate + 2 NADP+ + CoA(via HMG CoA reductase) **rate-limiting**
mevalonate + 2 ATP → mevalonate-5-diphosphate → isopentenyl diphosphate
isopentenyl diphosphate + dimethylallyl PP → geranyl PP + isopentenyl PP → farnesyl PP
2 farnesyl PP + 2 NADPH → squalene + 2 NADP+
Squalene is then cyclized to a sterol, which is then converted in a series of steps to cholesterol.
2. Understand the regulation of cholesterol biosynthesis and potential drug therapy targets.
As HMG-CoA reductase catalyzes the rate-limiting step, it is usually the target for regulation. High levels of cholesterol lead to decreased synthesis and increased degradation of HMG-CoA reductase. It can also be inactivated via phosphorylation by a glucagon-stimulated kinase, and desphosphorylation is favored by high insulin levels. Statins can block its function.
3. Compare the structures of bile salts and steroid hormones with cholesterol and understand how the former are derived from cholesterol.
Bile salts are made up of the basic four-ring structure of cholesterol, except the double bonds are reduced and hydroxyl groups are added. The carbon chain is also shortened, with a carboxyl group added at the end. The rate-limiting step in bile acid synthesis is the introduction of a hydroxyl group at carbon 7 of the steroid ring by cholesterol-7-alpha-hydroxylase. This is an ER associated enzyme found only in the liver, is down-regulated by cholic acid and up-regulated by cholesterol. Bile acids are conjugated to a molecule of glycine or taurine between the amino group and the carboxyl group on the acid.
Steroids are made up of the steroid nucleus of cholesterol with differing side groups containing oxygen.
4. Know the diseases associated with defects in the synthesis of cholesterol and its derivatives.
Smith-Lemli-Opitz syndrome – one of the most common autosomal recessive disorders in the North American population. Deficiency of the ultimate step in cholesterol biosynthesis is suspected. Plasma cholesterol decreases and precursor 7-dehydrocholesterol accumulates. Results in growth retardation, developmental delay, micocephaly, polyactyly, low-set ears, cleft palate, webbing between 2nd and 3rd toes, cataracts, undescended testes, drooping eyelids, heart defects, small chin.
5. Understand the synthesis and physiological role of Vitamin D.
Initial formation of cholecalciferol from cholesterol in skin (via UV light). Hydroxylation in liver and kidney yields active form of the vitamin, 1,25-dihydroxylcholecalciferol (calcifetriol).Vitamin D binds to an intracellular receptor. This complex then binds to DNA and regulates gene expression. The main action is to maintain adequate calcium plasma levels by promoting Ca2+ absorption from the gut, minimizing loss by kidney, and (to a lesser extent) mobilizing it from bone.
6. Understand the regulation of plasma calcium levels by PTH and calcitonin.
PTH is secreted by the parathyroid in response to low plasma calcium. It stimulates kidney synthesis of vitamin D, which promotes calcium reabsorption in the kidney and mobilization from bone. Calcitonin is secreted by cells in the connective tissue, between thyroid follicles, in response to high plasma calcium. It acts to increase kidney excretion and lower bone resorption.
7. Know the relationships between the key steroid hormones.
Cholesterol is converted into progesterone first. Progesterone can then give rise to three 'families' of steroids: testosterone and estradiol; cortisol; and corticosterone and aldosterone.
8. Understand the general mechanism of steroid hormone action on transcription and contrast this with that of peptide hormones.
Steroid hormones diffuse through the cell membrane and bind to specific nuclear receptors (hormone-dependent transcription factors). These complexes recognize a specific regulatory DNA sequence and activate the transcription of the target gene. Peptide hormones affect transcription only through a cascade of reactions, such as those arising from a G-protein coupled receptor.
9. Know the diseases associated with defective steroid synthesis.