Liver in biosynthesis

Dominant Role of the Liver in Biosynthesis of the Plasma Proteins with Special Reference to the Plasma Mucoproteins (Seromucoid), Ceruloplasmin, and Fibrinogen... 

Wang, X. D., R. M. Russell, C. Liu et al. 1996. Beta-oxidation in rabbit liver in vitro and in the perfused ferret liver contributes to retinoic acid biosynthesis from beta-apocarotenoic acids. J Biol Chem 271 (43) 26490-26498. 

Proteins are constantly being lost via the intestine and, to a lesser extent, via the kidneys. To balance these inevitable losses, at least 30 g of protein have to be taken up with food every day. Although this minimum value is barely reached in some countries, in the industrial nations the protein content of food is usually much higher than necessary. As it is not possible to store amino acids, up to 100 g of excess amino acids per day are used for biosynthesis or degraded in the liver in this situation. The nitrogen from this excess is converted into urea (see p. 182) and excreted in the urine in this form. The carbon skeletons are used to synthesize carbohydrates or lipids (see p. 180), or are used to form ATP. 

Miller, L. L., John, D. W. Nutritional, hormonal, and temporal factors regulating net plasma protein biosynthesis in the isolated perfused rat liver. In Plasma protein metabolism, pp. 207. Rothschild, M. A., Waldmann, T. (eds.). New York, London Academic Press 1970... 

A standard treatment is the administration of a large dose of propionate which is presumably effective because of the ease of its conversion to oxaloacetate via the methylmalonyl-CoA pathway. It is possible that this pathway was developed by animals as a means of capturing propionyl units, scanty though they may be, for conversion to oxaloacetate and use in biosynthesis. In ruminant animals, the pathway is especially important. Whereas we have 5.5 mM glucose in our blood, the cow has only half as much, and a substantial fraction of this glucose is derived, in the liver, from the propionate provided by rumen micro-... 

The second reduction step in biosynthesis of fatty acids in the rat liver (step i) also required NADPH. 

The hereditary absence of phenylalanine hydroxylase, which is found principally in the liver, is the cause of the biochemical defect phenylketonuria (Chapter 25, Section B).430 4308 Especially important in the metabolism of the brain are tyrosine hydroxylase, which converts tyrosine to 3,4-dihydroxyphenylalanine, the rate-limiting step in biosynthesis of the catecholamines (Chapter 25), and tryptophan hydroxylase, which catalyzes formation of 5-hydroxytryptophan, the first step in synthesis of the neurotransmitter 5-hydroxytryptamine (Chapter 25). All three of the pterin-dependent hydroxylases are under complex regulatory control.431 432 For example, tyrosine hydroxylase is acted on by at least four kinases with phosphorylation occurring at several sites.431 433 4338 The kinases are responsive to nerve growth factor and epidermal growth factor,434 cAMP,435 Ca2+ + calmodulin, and Ca2+ + phospholipid (protein kinase C).436 The hydroxylase is inhibited by its endproducts, the catecholamines,435 and its activity is also affected by the availability of tetrahydrobiopterin.436... 

Fibrinogen Biosynthesis by Isolated Liver. In our isolated rat liver perfusion studies homologous heparinized oxygenated rat blood is routinely diluted with Ringer s solution, so that its final volume is in-... 

The view that this is true net biosynthesis of fibrinogen is supported by a variety of ancillary observations. Fibrinogen biosynthesis is suppressed in the presence of metabolic analogs, such as L-ethionine and puromycin, most markedly by the latter in spite of the maximal stimulus for production. Mitomycin C, which is believed to interfere with biosynthetic processes in the nucleus, also caused some suppression of fibrinogen biosynthesis. The isolated perfused liver in the presence of any of the three inhibitors used continues to function in an apparently normal manner in terms of bile secretion, linear urea production, amino acid oxidation, and glucose utilization. The effects of these inhibitors on the biosynthesis of the other plasma proteins will be described elsewhere. 

From a strict biochemical point of view a clear-cut definition of the role of the liver in the biosynthesis of any particular plasma protein can be made only when the particular protein has been clearly and cleanly isolated, as in the case of fibrinogen. The practical difficulties of effecting such isolations on a small scale from isotopic labeling studies of the plasma proteins, such as we have described, seriously militate against such a detailed demonstration at present. The use of fractionation techniques with greater resolving power such as acrylamide gel electrophoresis already show some promise in our laboratory toward affording a more definitive picture of the biosynthetic role of the liver and the nonhepatic tissues in plasma protein production. 

The exclusive role of the liver in the biosynthesis of fibrinogen, questioned by some, has been reaffirmed in isolated liver perfusion experiments in which maximal net biosynthesis of fibrinogen of 0.6 mg. per hour per gram wet weight of liver occurs. This approximates three to four times the normal rate of fibrinogen biosynthesis in turnover in the intact normal rat and occurs only in liver perfusions in which the stimulus of extreme hypofibrinogenemia associated with the use of completely defibrinated blood is present. 

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