Plasma protein hepatic synthesis

Albumin (69 kDa) is the major protein of human plasma (3.4-4.7 g/dL) and makes up approximately 60% of the total plasma protein. About 40% of albumin is present in the plasma, and the other 60% is present in the extracellular space. The liver produces about 12 g of albumin per day, representing about 25% of total hepatic protein synthesis and half its secreted protein. Albumin is initially synthesized as a preproprotein. Its signal peptide is removed as it passes into the cisternae of the rough endoplasmic reticulum, and a hexapeptide at the resulting amino terminal is subsequently cleaved off farther along the secretory pathway. The synthesis of albumin is depressed in a variety of diseases, particularly those of the liver. The plasma of patients with liver disease often shows a decrease in the ratio of albumin to globulins (decreased albumin-globuhn ratio). The synthesis of albumin decreases rela-... 

Activators and inhibitors regulate not the amount of enzyme protein but the activity ( efficiency ) of that which is present. Two principal mechanisms of control are (i) competitive and (ii) allosteric. Competitive control (inhibition) occurs when a compound which is structurally similar to the true substrate binds to the active site of the enzyme. This is how a number of drugs and poisons bring about their effect. For example, a group of therapeutic drugs called statins are used to treat heart disease because by inhibiting a key enzyme called HMGCoA reductase, they reduce the hepatic synthesis of cholesterol and therefore the plasma concentration of that lipid. 

Pharmacology Vitamin K promotes the hepatic synthesis of active prothrombin (factor II), proconvertin (factor VII), plasma thromboplastin component (factor IX), and Stuart factor (factor X). The mechanism by which vitamin K promotes formation of these clotting factors involves the hepatic post-translational carboxylation of specific glutamate residues to gamma-carboxylglutamate residues in proteins involved in coagulation, thus leading to their activation. 

The central event in the development of liver fibrosis is the enhanced sinusoidal deposition of extracellular matrix proteins that are mainly produced by activated HSC [86, 112, 113] and to a minor extent by endothelial cells [44-46] and hepatocytes [114, 115]. So far, no evidence has been found that KC are directly involved in the production of extracellular matrix proteins [39]. The accumulation of extracellular matrix proteins is caused by a disturbed balance between the synthesis and the degradation of the matrix proteins. This imbalance leads to a 5 to 10-fold increase in the total amount of matrix molecules and to an altered composition of the extracellular matrix. In contrast to normal livers, the sinusoids in fibrotic livers are stuffed with the fibrillar collagens type I and III. This colla-genization of the sinusoids, referred to as sinusoidal capillarization, causes severe disturbances of the blood flow and an impaired exchange of proteins between the liver cells and blood. Furthermore, this capillarization is accompanied by a loss of fenestration of the sinusoidal endothelial lining, which further hampers the diffusion of proteins between plasma and hepatic cells. 

Baseline levels of urea and creatinine can be highly variable. Plasma urea reflects hepatic synthesis rate and will be elevated with increased protein catabolism (increased dietary protein intake, gastrointestinal hemorrhage, fever, severe bums, corticosteroid administration, sustained exercise or muscle wasting),... 

Rates of hepatic synthesis of many plasma proteins are affected by a patient s endocrine status. The effects of some steroid hormones on individual plasma protein levels are given in Table 20-5. The plasma protein levels characteristic of a specific disease may therefore be complicated by the steroid status of a patient and by an inflammatory acute phase reaction. The abnormal steroid status may be the result of an intrinsic hormonal disorder or of treatment with steroid hormones, as in inflammation. 

For hospital patients with infections, and after accidental injury or postsurgery, the systemic inflammatory response wiU affect the concentration of essential elements in circulating blood independently of nutritional status. For example, the APR causes increased permeability of capillaries and transfer of certain plasma carrier proteins and their trace metals into interstitial space. Hepatic synthesis of some plasma proteins, the so-called acute phase proteins, is also induced, so that these proteins increase in concentration in plasma, together with any metals that they carry (e.g., ceruloplasmin and copper). Moreover, there are marked changes in the kinetics of elements, with altered rates of transfer to and from the tissue. Knowledge of the effect of disease on metal kinetics and distribution is therefore essential. ... 

One of the smallest and the most abundant plasma proteins, albumin plays a significant role in osmotic regulation and transport of free fatty acids. Albumin is synthesized in the liver at a rate of approximately 14 g/d, or 10% of the total protein synthesis of the body. Deviations from the normal concentration of albumin in plasma can indicate the state of hepatic function. Albumin is also present in interstitial fluid. 

In considering how L-tryptophan can affect various organs, it is appropriate to review how it affects protein synthesis in specific organs. In addition to reports that tryptophan stimulates hepatic and plasma protein synthesis as described in Chapter 4, it has also been reported that tryptophan stimulates protein synthesis in other organs. These studies, other than in liver, are cited in this section. 

Albumin is the major plasma protein and is synthesized and secreted by the liver. It accounts for about. S09F of the total hepatic proiein production. Albumin has a biological half-life in plasma of about 20 days and a significant decrease in albumin concentration in plasma is slow to occur if there is reduced synthesis. Albumin makes the biggest contribution to the plasma... 

Effects on hepatic protein synthesis are caused by many hepatotoxins, but the changes may take some time to become apparent given the half-lives of the involved proteins. Reductions of plasma albumin and acid glycoprotein may affect the binding and exposures to xenobiotics and plasma bilirubin. Other effects on proteins may also be due to reduced food intake due to toxicity. The production of many plasma proteins, including those involved in complement and coagulation cascades, can be affected by reductions of hepatic protein synthesis. 

All of the information obtained on the amounts and patterns of urinary proteins should be interpreted, together with plasma measurements—particularly for evidence of glomerular nitration changes—and altered hepatic protein synthesis. For example, loss of large amounts of urinary albumin may result in hypoalbuminemia, or the hypoalbumineamia may reflect reduced hepatic synthesis with no evidence of marked changes of renal clearance of albumin. 

It is important to distinguish between changes in zinc metabolism which occur as a secondary effect of disease, injury, infection and drug therapy and alterations caused by a primary nutritional zinc deficiency. There is confusion in the literature because a number of unrelated causes can temporarily lower the concentration of zinc in plasma, and this is reported uncritically as evidence of nutritional depletion. Since a high proportion of zinc in plasma is albumin bound, any circumstance which lowers plasma albumin wiil also lower plasma zinc. For example, the changes seen in severe liver disease are primarily caused by a failure of hepatic synthesis of plasma proteins such as albumin. This results in problems in the distribution of zinc and eventual tissue depletion. It is questionable whether zinc supplementation of diet is worthwhile without some restoration of hepatocyte function, by effective treatment of the underlying disease (Mills et al., 1983). 

Plasma P-lipoprotein concentration in rats receiving orotic acid falls to less than 1% of normal and rebounds to normal level within 48 hours following withdrawal of orotic acid [300]. When perfused in situ, the livers from orotic acid fed rats released a-lipoprotein, albumin, and other plasma proteins but no detectable p-lipoprotein. They also released smaller amounts of cholesterol and phospholipids than normal livers and no triglycerides, although they contained ten times the normal amount of triglycerides [300]. Since p-lipoprotein has a specific role in the normal transport of triglycerides, the fatty liver produced by orotic acid appears to result from the inhibition of synthesis or release of hepatic P-lipoprotein. 

Bilirubin resulting from the breakdown of haemoglobin in the cells of the reticulo-endothelial system passes into the blood plasma where it circulates in combination with the ai-globulin fraction from there it passes into the cells of the hepatic parenchyma which conjugate the bilirubin with glucuronic add and excrete the product in the bile. Furthermore the hepatic parenchyma is the site of considerable protein synthesis, that of the blood plasma proteins. 

Zinc represents another nutrient whose nutritional status may influence plasma vitamin A and RBP levels in malnourished children. Interrelationships between zinc and vitamin A have been reviewed in detail by Solomons and Russell (1980) and by Smith (1980), and are discussed and summarized in Chapter 6, Vol. 1. Studies in experimental animals have shown that zinc deficiency is associated with low plasma vitamin A and RBP levels. It has been suggested that this may be due in part to impaired hepatic synthesis of RBP (Smith et al., 1974). This effect on RBP production has not been thought to be in any way specific for RBP rather hepatic synthesis of plasma proteins in general appears to be impaired in zinc deficiency, with RBP being one of the hepatic proteins most sensitive to this deficiency. The main effect of zinc deficiency on vitamin A and RBP metabolism appears, however, to be secondary to the depressed food intake... 

---