Biochemistry - The Chemical Reactions of Living Cells Volume 2 - D. Metzler 1980

Biosynthesis: How New Molecules Are Formed
Steroid Compounds
Cholesterol Metabolism

Cholesterol enters The Human Body through intestinal absorption and is also synthesized in the Liver from acetate via The intermediate formation of squalene. High concentrations of cholesterol are found not only in the Brain and other neural Tissues, but also in Blood Plasma, where its concentration is about 1.7 g/L. Approximately ²/₃ of this amount is in an esterified form, predominantly as esters of Unsaturated Fatty acids. Blood cholesterol levels depend heavily on diet, age, and sex. By age 55, cholesterol levels rise on average to 2.5 g/L, though they can be significantly higher; premenopausal women have markedly lower blood cholesterol levels than men.

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FIG. 12-16 Formation of Bile acids.

The majority of plasma cholesterol is bound to low-density lipoprotein (LDL; Appendix 2-A), which delivers cholesterol esters directly to target Cells. The cholesterol–LDL complex binds to specific LDL receptors on The Cell surface and is subsequently internalized via endocytosis [97b]. The lipoprotein is then subjected to lysosomal Enzymes, and a specific acidic lipase hydrolyzes the cholesterol esters to release free cholesterol. Cellular cholesterol uptake is regulated by a feedback mechanism that controls the synthesis rate of LDL receptor molecules. In addition, free cholesterol inhibits a key step in its own Biosynthesis—the reduction of 3-hydroxy-3-methylglutaryl-CoA (Fig. 11-8) [97b, 97c]. Several disorders of cholesterol METABOLISM are known. One form of familial hypercholesterolemia involves a hereditary alteration in The properties of the LDL receptor protein, which impairs normal LDL binding and cholesterol ester uptake. Another condition is cholesterol ester storage disease, caused by a deficiency of lysosomal acid lipase. Further study of this aspect of metabolism is of great importance, as it may shed light on the Pathogenesis of atherosclerosis ("hardening of the Arteries"), a highly prevalent human disease [97d].

In the body, cholesterol is converted into A number of substances, including Steroid Hormones. Quantitatively, however, the most important products of cholesterol conversion are bile acids (Fig. 12-16). These powerful emulsifying agents pass from the liver into the Gallbladder and subsequently into the duodenum. A significant portion of the secreted bile acids is later reabsorbed in the intestine, returned to the liver, and reused. The formation of bile acids involves the removal of the double bond in cholesterol, inversion at C-3 to form the 3α-OH group, followed by hydroxylation and β-oxidation of the side chain. Next, bile acids (or their CoA derivatives) are conjugated with Glycine or taurine to form bile salts—glycocholic or taurocholic acids (Fig. 12-16).