Liver plasma protein biosynthesis

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... 

Biosynthesis of endogenous compounds and storage, conversion, and degradation of them into excretable molecules (metabolism). In particular, the liver is responsible for the biosynthesis and degradation of almost all plasma proteins. 

Each hormone is the center of a hormonal regulation system. Specialized glandular cells synthesize the hormone from precursors, store it in many cases, and release it into the bloodstream when needed (biosynthesis). For transport, the poorly water-soluble lipophilic hormones are bound to plasma proteins known as hormone carriers. To stop the effects of the hormone again, it is inactivated by enzymatic reactions, most of which take place in the liver (metabolism). Finally, the hormone and its metabolites are expelled via the excretory system, usually in the kidney (excretion). All of these processes affect the concentration of the hormone and thus contribute to regulation of the hormonal signal. 

Amino Acids Amino acids that enter the liver follow several important metabolic routes (Fig. 23-14). (1) They are precursors for protein synthesis, a process discussed in Chapter 27. The liver constantly renews its own proteins, which have a relatively high turnover rate (average half-life of only a few days), and is also the site of biosynthesis of most plasma proteins. (2) Alternatively amino acids pass in the bloodstream to other organs, to be used in the synthesis of tissue proteins. (3) Other amino acids are precursors in the biosynthesis of nucleotides, hormones, and other nitrogenous compounds in the liver and other tissues. 

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

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. 

Each tissue, including the bloodstream, has a free amino acid pool. This amounts to a total of about 100 g. By far the largest fraction, 50-80%, is located in muscle. Kidney accounts for about 4%, liver for 10%, and the bloodstream another 4%. Glutamine and glutamate are major components of such pools. Free amino acid pools are in equilibrium with tissue protein. Tissue proteins are in a constant state of turnover, that is, biosynthesis and degradation from and to free amino acids. Only plasma proteins, which are largely synthesized in the liver, are not in equilibrium with the plasma free amino acid pool. 

It is now well established that very low density and low density lipoproteins are synthesized in the liver. Data supporting this conclusion have been obtained from studies on plasma triglyceride metabolism, the fatty liver and its origin, and protein biosynthesis in the liver. Many of the studies used animals which have a somewhat different lipoprotein pattern than the human. Metabolic sequences differ in detail between species and unique model systems are required (Farquhar et al. 1965). Nevertheless fundamental aspects of lipoprotein metabolism such as liver synthesis have been confirmed in several animals. 

Plasma proteins are manufactured in the liver and their serum levels are reduced when the ability of hepatocytes to synthesize proteins is impaired. The ammonia level rises when hepatocyte damage prevents biosynthesis of amnrania to urea. Bilirubin can increase as a result of either hepatocyte dysfunction or cholestasis. Prothrombin time increases because of the reduced availability of coagulation factors normally synthesized by hepatocytes. Sorbitol dehydrogenase (SDH) is a liver-specific enzyme that is released when... 

Mechanism of Action An HMG-CoA reductase inhibitor that interferes with cholesterol biosynthesis by preventing the conversion of HMG-CoA reductase to meva-lonate, a precursor to cholesteroh Therapeutic Effect Lowers serum LDL and VLDL cholesterol and plasma triglyceride levels increases serum HDL concentration. Pharmacokinetics Poorly absorbed from the G1 tract. Protein binding 50%. Metabolized in the liver (minimal active metabolites). Primarily excreted in feces via the biliary system. Not removed by hemodialysis. Half-life 2.7 hr. 

Carnitine biosynthesis utilizes the essential amino acid lysine, with terminal methyl groups donated by S-adenosylmethionine. Only lysine incorporated into proteins is a substrate for the methylation reaction. In humans, the final reaction in the biosynthetic pathway, catalyzed by a cytosolic hydroxylase, occurs in liver and kidney but not in cardiac or skeletal muscle. The carnitine requirement of these tissues is met by carnitine transported to them via the plasma... 

The amino acid pool (600-700 g) is distributed among the musculature (80%), the liver (15%) and the plasma (5%). The proportion of free amino acids merely amounts to about 0.5% of the total amino acids contained in the body proteins. Of this amount, 300-500 g are used daily for protein synthesis, and approx. 2 g are used for the synthesis of other N-containing compounds (e. g. purines, porphyrins, pyrimidines) a further 120-130 g are degraded per day. This daily amino acid consumption is replaced from three sources, so that the amino acid pool is maintained at a constant level (7.) 70-100 g should be contained in the diet, (2.) 300-500 g derive from protein degradation, and (3.) 30-40 g are replenished from the biosynthesis of non-essential amino acids. The essential amino acids released by proteolysis are utilized as rapidly and completely as possible in the neosynthesis of proteins (= recycling of essential amino acids). 

The rate at which cholesterol and triglycerides enter the circulation from the liver and small intestine depends on the supply of the lipid and proteins necessary to form the lipoprotein complexes. Although the protein component must he synthesized, the lipids can be obtained either from de novo biosynthesis in the ti.ssucs or from the diet. Reduction of plasma lipids by diet can delay the development of atherosclerosis. Furthermore, the u.sc of drugs that decrease assimilation of lipids into the body plus diet decreases mortality from cardiovascular disca.se. ... 

Cholesterol travels in the bloodstream via lipoprotein complexes called Chylomicrons, VLDL, IDL, LDL, and HDL. Of the five lipoprotein classes, LDL is by far the richest in cholesterol. Cholesterol in plasma lipoproteins exists both as the free sterol and esterified at its hydroxyl position with a long-chain fatty acid, usually unsaturated (see also Table 18.1). The LDL particle contains a single molecule of apoprotein B-lOO (Mr = 513,000) as its primary protein component. Because cholesterol biosynthesis is confined primarily to the liver with some occurring also in intestine, LDL plays an important role in delivering cholesterol to other tissues. Cholesterol esters are too hydrophobic to traverse cell membranes by themselves and must be transported into cells via specialized LDL receptors. 

The relevance of the results obtained in vitro, in either liver slices or perfusates, to the general problem of lipoprotein biosynthesis in the intact animal remains to be established. In vivo synthesis of the protein moiety of serum 3-lipoprotein was studied in roosters by administration of S -methionine (Florsheim et al., 1963), followed by measurements of specific radioactivity of plasma 3-lipoprotein separated by dextran sulfate. Under these experimental conditions, enhancement of methionine incorporation was noted after pharmacological doses of ethanol, estrogens, and triiodothyronine. No significant effect was obtained after administration of epinephrine, cortisone, and thyroxine preparations. 

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