Calcium-regulating sterol

Calcium-regulating sterols control the resorption of calcium ions into the gastro-intestinal tract, and influence bone metabolism. Vitamin D3 (chole-calciferol), generated by photolysis of 7-dehydrocholesterol, is its most prominent member. 

Calcium homeostasis is modulated by hormones (Fig. 2). Parathyroid hormone (PTH) is the most important calcium regulator. It is a hormone of 84 amino acids, and is secreted from the parathyroid glands in response to a low unbound plasma calcium. PTH causes bone resorption and promotes calcium reabsorption in the renal tubules, preventing loss in the urine. 1,25-dihydroxycholecalciferol (1.23 DHCC) maintains intestinal calcium absorption. This sterol hormone is formed from vitamin D (cholecalciferol). following hydroxylation in the liver (at carbon-25) and kidney (at carbon-1). However.hydroxylation in the kidney is PTH dependent.andsoeven (he absorption of calcium from the gut relies (albeit indirectly) on PTH. 

The D vitamins are a group of sterols that have a hormone-like funciion. The active molecule, 1,25-dihydroxycholecalciferol (1,25 diOH D3), binds to intracellular receptor proteins. The 1,25-diOH D3-receptor complex interacts with DNA in the nucleus of target cells in a manner simiar to that of vitamin A (see Figure 28.20), and either selectively stimulates gene expression, or specifically represses gene transcription. The most prominent actions of 1,25-diOH D3 are to regulate the plasma levels of calcium and phosphorus. 

Sterol-specific cytoplasmic receptor proteins (vitamin D receptor) mediate the biological action of vitamin D (9). The active hormone is transported from the cytoplasm to the nucleus via the vitamin D receptor, and as a result of the interaction of the hormone with target genes, a variety of proteins are produced that stimulate the transport of calcium in each of the target tissues. Active vitamin D works in concert with PTH to enhance active intestinal absorption of calcium, to stimulate bone resorption, and to prohibit renal excretion of calcium (2,9). If serum calcium or 1,25-calcitriol concentrations are elevated, then vitamin D 24-hydroxylase (in renal mitochondria) is activated to oxidize 25(OH)D3 to inactive 24,25-dihydroxy-cholecalciferol and to further oxidize active vitamin D to the inactive 1,24,25-trihydroxylated derivative. Both the 1,24,25-trihydroxylated and the 24,25-dihydroxylated products have been found to suppress PTH secretion as well. Several factors have been identified in the regulation of the biosynthesis of vitamin D, including low phosphate concentrations (stimulatory) as well as pregnancy and lactation (stimulatory). 

Researchers have studied whether acyl-chain order could be responsible for the preferred sterol interaction with SMs. Acyl-chain order was deduced from diphenylhexatriene anisotropy and from the deuterium order parameter obtained by H-NMR on bilayers made from either 14 0/14 0(d27)-PC, or 14 0(d27)-SM7 Some researcher analyzed the ground and excited states of phospholamban (PLN), a membrane protein that regulates sarcoplasmic reticulum (SR) calcium ATPase (SERCA), in dilferent membrane mimetic environments. Gustavsson et al. have previously proposed that the conformational equilibrium of PLN are central to SERCA regulation. They have now shown that these equilibrium detected in micelles and bicelles are also present in native sarcoplasmic reticulum lipid membranes as probed by MAS solid-state NMR. ... 

A variety of lipid molecules take part in diverse aspects of metabolism and its control. Polyunsaturated fatty acids and their metabolites have been discussed above. Others are the fat-soluble vitamins, retinol (vitamin A) and tocopherol (vitamin E) (Chapters 5 and 8). Sterols, such as cholesterol, regulate membrane function and act as precursors for a range of molecules with diverse metabolic activities cholecalciferol (vitamin D), which is metabolized further to hydroxylated derivatives that regulate calcium metabolism and other aspects of cellular function (Chapters 5 and 7) bile acids, which are involved in lipid absorption (Chapters 4 and 7) and steroid hormones (Chapter 7). 

A major role of vitamin D is to maintain the concentrations of calcium and phosphorus in the blood, primarily by enhancing the absorption of dietary calcium from the alimentary tract and regulating the interchange of calcium between blood and bone. It is likely that there are other cellular roles as yet little understood. The active form of vitamin D responsible for the hormone-like functions described above is 1,25-dihydroxycholecalciferol. Cholecalciferol, whether absorbed from the diet or synthesized in the skin, is first hydroxylated in the liver to 25-hydroxycholecalciferol. This is the main form of the hormone circulating in the blood, bound to a sterol binding protein. A further hydroxylation occurs in the kidneys to give 1,25-... 

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