Chapter 26: Biosynthesis of Membrane Lipids & Steroids

The exploration begins with the formation of phosphatidate, a pivotal intermediate derived from glycerol 3-phosphate and fatty acyl CoA, which serves as a precursor for both storage lipids (triacylglycerols) and membrane lipids (phosphoglycerides). The text elucidates the requirement for activated intermediates, such as CDP-diacylglycerol or CDP-alcohols, in the synthesis of major phospholipids like phosphatidylinositol, phosphatidylethanolamine, and phosphatidylcholine, highlighting the regulatory influence of phosphatidic acid phosphatase (lipin 1). The discussion extends to sphingolipids, synthesized from a ceramide backbone, and examines the clinical implications of metabolic failures, such as respiratory distress syndrome caused by dipalmitoylphosphatidylcholine deficiency and lysosomal storage disorders like Tay-Sachs disease. A central focus is placed on cholesterol biosynthesis, a complex process converting acetyl CoA into the steroid nucleus via mevalonate and squalene. Detailed attention is given to the regulation of HMG-CoA reductase through the SREBP pathway, proteolysis, and phosphorylation, as well as the pharmacological inhibition of this enzyme by statins. The chapter further explores lipid transport through plasma lipoproteins (chylomicrons, VLDL, LDL, and HDL) and the mechanism of receptor-mediated endocytosis, illustrating how defects in the LDL receptor lead to familial hypercholesterolemia and atherosclerosis. Finally, the text covers the metabolic conversion of cholesterol into vital derivatives, including bile salts for lipid digestion, Vitamin D via UV photolysis, and the five classes of steroid hormones—progestogens, glucocorticoids, mineralocorticoids, androgens, and estrogens—mediated by cytochrome P450 monooxygenases.