7 - Dehydrocholesterol membranes

Vitamin D is a fat soluble vitamin derived from cholesterol. In the human epidermis (skin), sunlight spontaneously oxidizes cholesterol to 7-dehydrocholesterol (Fig. 10.10a). The 7-dehydrocholesterol leaks into the blood where it isomerizes to cholecalciferol (vitamin D3, Fig. 10.10b and c). Cholecalciferol is enzymatically hydroxylated at C25 in the liver (25-cholecalciferol) and then passes to the kidney where another enzyme is activated by parathyroid hormone to hydroxylate it at Cl, forming calcitriol (Fig. lO.lOd). The kidney hydroxylase is sensitive to feedback inhibition. As the amount of calcitriol increases, it binds to the hydroxylase and alters the specificity of the kidney enzyme. Additional 25-cholecal-ciferol is hydroxylated to 24,25-dihydroxycholecalciferol (inactive calcitriol) instead of 1,25 dihydroxycholecalciferol (calcitriol). Other vitamin D derivatives that can be converted to calcitriol are obtained enzymatically from cholesterol in other vertebrates. The most common of these are vitamin D3 (lamisterol) and D2 (ergosterol) from cold-water fish such as cod, where their presence keeps membranes fluid at low body temperatures 10-20°C. 

Phospholipids and glycosphingolipids are amphipathic lipid constituents of membranes (Chapter 10). They play an essential role in the synthesis of plasma lipoproteins (Chapter 20) and eicosanoids (Chapter 18). They function in transduction of messages from cell surface receptors to second messengers that control cellular processes (Chapter 30) and as surfactants. Cholesterol is mainly of animal origin and is an essential constituent of biomembranes (Chapter 10). In plasma, cholesterol is associated with lipoproteins (Chapter 20). Cholesterol is a precursor of bile acids formed in the liver of steroid hormones secreted by adrenals, gonads, and placenta and 7-dehydrocholesterol of vitamin D formed in the skin. In tissues, cholesterol exists primarily in the unesterified form (e.g., brain and erythrocytes), although appreciable quantities are esterified with fatty acids in liver, skin, adrenal cortex, and plasma lipoproteins. 

Cholesterol biosynthesis proceeds via the isoprenoids in a multistep pathway. The end product, cholesterol, and the intermediates of the pathway participate in diverse cellular functions. The isoprenoid units give rise to dolichol, CoQ, heme A, isopentenyl-tRNA, famesylated proteins, and vitamin D (in the presence of sunlight and 7-dehydrocholesterol). Dolichol is used in the synthesis of glycoproteins, CoQ in the mitochondrial electron transport chain, famesylation and geranylgeranylation by posttrans-lational lipid modification that is required for membrane association and function of proteins such as p2V and G-protein subunits. 

Cholesterol is utilized in formation of membranes (Chapter 10), steroid hormones (Chapters 30,32, and 34), and bile acids. 7-Dehydrocholesterol is required for production of vitamin D (Chapter 37). Under steady-state conditions, the cholesterol content of the body is maintained relatively constant by balancing synthesis and dietary intake with utilization. The major consumer of cholesterol is formation of bile acids, of which about 0.8-1 g/day are produced in the liver and lost in the feces. However, secretion of bile acids by the liver is many times greater (15-20 g/day) than the rate of synthesis because of their enterohepatic circulation (Chapter 12). Cholesterol is also secreted into bile, and some is lost in feces as cholesterol and as coprostanol, a bacterial reduction product (about 0.4-0.5 g/day). Conversion of cholesterol to steroid hormones and of 7-dehydrocholesterol to vitamin D and elimination of their inactive metabolites, are of minor significance in the disposition of cholesterol, amounting to approximately 50 mg/day. A small amount of cholesterol... 

Previous investigations from several laboratories have demonstrated that both microsomal membranes and the cytosolic fraction from rat hver are required for the biological synthesis of cholesterol [1-4]. Specifically, the following conversions have been reported to require both microsomes and cytosol acetate to cholesterol [4] squalene to cholesterol [1] squalene-2,3-oxide to lanosterol [3] lanosterol to cholesterol [1,5] A -cholestenol to cholesterol [6] lanosterol to dihydrolanosterol [7] various 4,4-dimethyl sterols to cholesterol [8] and 7-dehydrocholesterol to cholesterol [9,10]. 

Although cholesterol is always the major sterol present, a few closely related sterols are detected in mammalian cells, namely 7-dehydrocholesterol (cholest-5,7-dien-3 -ol) [11], cholestanol (5a-cholestan-3j8-ol) [12,13], lathosterol (5a-cholest-7-en-3/8-ol) [14] and desmosterol (cholest-5,24-dien-3)8-ol) [15]. 7-Dehydrocholesterol can make up 6-9% of the sterol content in subcellular membranes and in skin [11]. The structures of the most relevant mammahan and plant sterols are given in Fig. 1. 

Sterols are important components in cell membranes and they are thought to function primarily in membrane structure stabilization (9). The sterols of P. purpureum are poorly known (10), partly because it seems to contain only small amounts of sterols because of this P, purpureum was originally thought to lack sterols (11). In the red algae, the dominant sterol is usually cholesterol, but desmosterol and 22-dehydrocholesterol have been found to be prominent in some species (12). rra/t5 22-dehydrocholesterol has been reported to be the dominant sterol in P. purpureum (10). 

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