Rate Of Hepatic Protein Synthesis Research Articles

Reduced invivo hepatic proteome replacement rates but not cell proliferation rates predict maximum lifespan extension in mice.

Combating the social and economic consequences of a growing elderly population will require the identification of interventions that slow the development of age-related diseases. Preserved cellular homeostasis and delayed aging have been previously linked to reduced cell proliferation and protein synthesis rates. To determine whether changes in these processes may contribute to or predict delayed aging in mammals, we measured cell proliferation rates and the synthesis and replacement rates (RRs) of over a hundred hepatic proteins invivo in three different mouse models of extended maximum lifespan (maxLS): Snell Dwarf, calorie-restricted (CR), and rapamycin (Rapa)-treated mice. Cell proliferation rates were not consistently reduced across the models. In contrast, reduced hepatic protein RRs (longer half-lives) were observed in all three models compared to controls. Intriguingly, the degree of mean hepatic protein RR reduction was significantly correlated with the degree of maxLS extension across the models and across different Rapa doses. Absolute rates of hepatic protein synthesis were reduced in Snell Dwarf and CR, but not Rapa-treated mice. Hepatic chaperone levels were unchanged or reduced and glutathione S-transferase synthesis was preserved or increased in all three models, suggesting a reduced demand for protein renewal, possibly due to reduced levels of unfolded or damaged proteins. These data demonstrate that maxLS extension in mammals is associated with improved hepatic proteome homeostasis, as reflected by a reduced demand for protein renewal, and that reduced hepatic protein RRs hold promise as an early biomarker and potential target for interventions that delay aging in mammals.

Alcohol—intoxicating roadblocks and bottlenecks in hepatic protein and lipid metabolism

with over 60% of the population consuming alcohol during the past year, and 32% admitting to engaging in alcohol binging episodes, alcohol abuse continues to be a comorbid condition for several diseases, but in particular for liver disease. Liver disease is one of the most salient pathophysiological

Dietary protein intake is an independent and dose‐dependent regulator of hepatic anabolism in rats fed high protein diets

We previously observed that drastic increases in protein consumption greatly modify hepatic protein anabolism in rats, yet the confounding effects of the other macronutrient changes and the ability of a moderate protein increase to produce the same effects are not established. This study examined the metabolic and hormonal responses of rats submitted to 14‐d isoenergetic diets with normal, intermediary or high protein levels (NP:14% of energy, IP: 33%, HP: 50%) and different carbohydrate (CHO) to fat ratios within each protein level. Fasted or fed rats (n=96) were killed after injection of a flooding dose of 13C‐valine. Hepatic protein content increased with the dietary protein level (P<0.05). The hepatic fractional synthesis rates (FSR) of protein were significantly influenced by both the protein level and the nutritional state (fasted vs. fed) (P<0.0001) but not by the CHO/fat ratio and reached on average 110%/d, 92%/d and 83%/d in rats fed the NP, IP and HP diets, respectively. Muscle FSR did not differ among diets. Insulin levels significantly decreased with both increasing protein level and decreasing CHO/fat ratio. Our results reveal that excess dietary protein inhibits hepatic protein synthesis rates independently of the other macronutrients and the related changes in insulin levels. This response is observed at moderate levels of protein intake (33%) that are plausible in human consumption.

Maslinic acid as a feed additive to stimulate growth and hepatic protein-turnover rates in rainbow trout ( Onchorhynchus mykiss)

Maslinic acid is a triterpene present in a considerable proportion in solid residues from olive-oil production. In the present work the effects of maslinic acid on growth, protein-turnover rates and nucleic-acid concentration on liver were investigated in the rainbow trout. Five groups of 120 fish of a mean body mass of 20 g were fed for 225 days with diets containing 0, 1, 5, 25 and 250 mg of maslinic acid per kg diet. At the end of the experiment, whole-body and liver weight and growth rate of trout fed with maslinic acid were higher than controls. The highest weight increase was registered for the group fed 250 mg kg − 1 , representing a 29% increase over controls. The total hepatic DNA or liver cell hyperplasia levels in trout fed with 25 and 250 mg of maslinic acid kg − 1 were 37% and 68% higher than controls. Also in these same groups of trout, fractional and absolute hepatic protein-synthesis rates were significantly higher than in control, and significant increments in hepatic protein-synthesis efficiency and protein-synthesis capacity were reported. In close agreement with these results, microscopy studies showed that trout fed on 25 and 250 mg kg − 1 hepatocytes appeared to be more compact, with a larger rough-endoplasmic reticulum and larger glycogen stores than controls. These results suggest that maslinic acid can act as a growth factor when added to trout diet.

Effect of growth hormone on muscle and liver protein synthesis in septic rats receiving glutamine-enriched parenteral nutrition.

Administration of recombinant human growth hormone (rhGH) to critically ill adults in an attempt to attenuate catabolism was associated with increased morbidity and mortality. Possible explanations included inhibition of glutamine release from skeletal muscle and consequent restriction of splanchnic glutamine supply. In this study, we examined the effects of rhGH on plasma glutamine levels and on muscle and liver glutamine concentrations and protein synthesis rates in sepsis. We investigated the possibility that administration of supplemental glutamine might ameliorate any adverse effects of rhGH. Prospective study in rats rendered septic by cecal ligation and puncture. University hospital laboratory. A total of 78 male Wistar rats in six groups. Animals received 6-hr tail vein infusions, commencing 18 hrs after cecal ligation and puncture, of either (a) 0.9% sodium chloride, (b) a standard parenteral nutrition (PN) solution without glutamine, or (c) an isocaloric, isonitrogenous PN solution with glutamine. PN groups received 400 microg rhGH or equivolume 0.9% sodium chloride vehicle in a divided subcutaneous and intravenous dose at PN commencement. Sacrifice was at the end of the infusion period. A further group was unoperated and uninfused and killed at 24 hrs as baseline controls. Glutamine concentrations were measured by fluorometry. Protein synthesis in muscle and liver was measured by a "flooding-dose" technique employing L-[4-H]phenylalanine. Plasma glutamine was increased after cecal ligation and puncture except in the saline and glutamine with rhGH animals. Muscle glutamine was reduced after cecal ligation and puncture and was significantly lower in animals receiving standard PN with rhGH vs. saline alone. Liver glutamine was increased in animals receiving saline and those receiving standard PN with rhGH. PN, with or without glutamine, increased muscle protein synthesis, and the administration of rhGH tended to further increase this effect. Neither PN, glutamine, nor rhGH had an effect on the increased liver protein synthesis characteristic of sepsis. In sepsis, increased muscle protein synthesis with PN and rhGH administration is not associated with increased muscle glutamine levels. Administration of rhGH does not result in reduced liver glutamine levels or rates of hepatic protein synthesis. PN containing glutamine was no more efficacious than standard PN at increasing muscle protein synthesis.

Estradiol impairs hyposmoregulatory capacity in the euryhaline tilapia, Oreochromis mossambicus.

Freshwater (FW)-adapted tilapia (Oreochromis mossambicus) were treated with estradiol (E(2)) for 4 days to stimulate protein synthesis and sampled at 0, 4, and 24 h after exposure to 50% seawater (SW). E(2) increased circulating vitellogenin (VTG) levels in large amounts, indicative of unusually high rates of hepatic protein synthesis. E(2) treatment prevented the recovery of plasma osmolality in 50% SW that was evident in the sham group. Plasma sodium concentration was significantly elevated with E(2) in FW, but the levels did not change in 50% SW. Gill Na(+)-K(+)-ATPase activity was significantly lower in the E(2) group compared with sham-injected tilapia in 50% SW. No significant differences were noted in plasma cortisol, thyroxine, triiodothyronine, or glucose concentration with E(2) in 50% SW. E(2) significantly lowered several key liver enzyme activities and also decreased gill lactate dehydrogenase and malate dehydrogenase activities over a 24-h period. Together, our results suggest that E(2) impairs ion regulation in tilapia, partially mediated by a decreased metabolic capacity in liver and gill. The decreased tissue metabolic capacity is likely due to E(2)-induced energy repartitioning processes that are geared toward VTG synthesis at the expense of other energy-demanding pathways.

Dietary Amino Acids Are the Preferential Source of Hepatic Protein Synthesis in Piglets

To investigate the utilization of dietary amino acids for hepatic protein synthesis, seven female pigs ( 28 d old, 7.5 kg) were implanted with catheters in a carotid artery, the jugular and portal veins, and the stomach. A portal flow probe was also implanted. The pigs were fed a high protein diet once hourly and infused intragastrically with [U-13C]algal protein for 6 h. Amino acid labeling was measured in arterial and portal blood, in the hepatic free and protein-bound pools and in apolipoprotein B-100 (apoB-100), albumin and fibrinogen. The isotopic enrichments of apoB-100–bound [U-13C]threonine, leucine, lysine and phenylalanine were 33, 100, 194 and 230% higher than those of their respective hepatic free amino acid pools (P < 0.01). Using the labeling of apoB-100 to estimate that of the protein synthetic precursor, the fractional rate of hepatic protein synthesis was 42 ± 2%/d. Between 5 and 8% of the dietary tracer amino acids was used for hepatic protein synthesis. In contrast to the small intestinal mucosa, in which the majority of the metabolized amino acids were apparently catabolized, protein synthesis utilized from 48% (threonine) to 90% (lysine) of the hepatic uptake of tracer amino acids. It appears that hepatic protein synthesis consumes nutritionally significant quantities of dietary essential amino acids in first pass and that extracellular, especially portal, essential amino acids are channeled to hepatic protein synthesis in the fed state.

A simultaneous study of the metabolism of apolipoprotein B and albumin in nephrotic patients

The nephrotic syndrome is characterized by proteinuria, hypoalbuminemia and hyperlipidemia. Despite intensive research it is not clear at present what the causal links are between these pathological findings. Stable isotope labeled amino acid tracer kinetic analysis was used to simultaneously investigate the metabolism of four apolipoprotein B-containing lipoproteins (VLDL1, VLDL2, IDL and LDL) and albumin in seven patients with nephrotic syndrome and marked hypercholesterolemia, in two additional nephrotic patients with concomitant renal failure and mixed hyperlipidemia, and in a matched group of normolipidemic controls. Increased concentrations of VLDL2, IDL and LDL were due to (a) impaired VLDL2 and IDL delipidation, (b) reduced LDL catabolism, and (c) a trend towards an increased rate of total apolipoprotein B production. The rate of fractional albumin elimination was three times higher in patients than in controls and the rate of albumin synthesis was increased by 45%. No correlations were detectable between rates of apolipoprotein B production and the rate of albumin synthesis. The results of this study suggest that hyperlipidemia in nephrotic syndrome is predominantly the result of delayed lipoprotein delipidation and catabolism. There is no evidence that it is driven by a general increase of the rate of hepatic protein synthesis.

Effects of zinc deficiency on protein synthesis and expression of specific mRNAs in rat liver

The effects of zinc deficiency on protein synthesis and expression of specific mRNAs were assessed in rat liver. Zinc deficiency had no apparent effect on liver weight, protein content, or RNA content when these properties were compared with values obtained using pair-fed rats. However, zinc deficiency resulted in a lower rate of hepatic protein synthesis. The decreased rate of protein synthesis was due to a decrease in the rate of synthesis of proteins retained in the liver, with no apparent change in the synthesis of secreted proteins. Analysis of expression of specific gene products, as assessed by in vitro translation of total RNA followed by two.dimensional gel analysis, showed that the expression of only a few mRNAs was altered by zinc deficiency. The patterns of change in gene expression resulting from zinc deficiency varied from almost complete repression to full expression. In additional studies, cDNA clones to serum retinol-binding protein and transthyretin were used to examine the effect of zinc deficiency on the relative abundance of mRNA for these two proteins. The relative abundance of mRNA for transthyretin was specifically elevated as a result of zinc deficiency. In contrast, the relative abundance of mRNA for hepatic serum retinol-binding protein was increased in both zinc-deficient and pair-fed rats. Therefore, the observed change in mRNA for serum retinol-binding protein was apparently at least in part due to the inanition that accompanies zinc deficiency. Overall, the results suggest that zinc can regulate the synthesis of specific proteins in rat liver through changes in the relative abundance of specific mRNAs.

タンパク質代謝の栄養制御

Regulatory mechanisms of hepatic protein metabolism and gene expression mediated by amino acids and vitamin B6 were investigated. 1) Rats were nourished by total parenteral nutrition, and the effects of variations in the amino acid supply on the rates of hepatic protein synthesis and degradation were investigated. Amino acids decreased the rate of degradation whilst the rate of synthesis was relatively unaffected. Protein degradation, therefore, predominates the regulation of liver protein mass. 2) Studies on cystathionase and aspartate aminotransferase (AspAT) in the liver of vitamin B6-deficient rats showed that their rates of synthesis and degradation were both increased. The enhanced degradation was caused by different susceptibilities of apo- and holo-enzymes to lysosomal proteolysis. 3) Pyridoxal phosphate (PLP) was found to modulate AspAT gene expression by preventing the glucocorticoid receptor from binding to glucocorticoid-responsive elements. PLP also modulated albumin gene expression by inactivat ng the DNA-binding activity of tissue-specific transcriptional factors such as HNF-1 and C/EBP. 4) Amino acid vinfusion increased the albumin mRNA level and decreased the PLP concentration. The decrease in PLP concentration would prevent the inactivation of tissue-specific transcription factors and enhance albumin gene expression. The present study sheds new light on the physiological role of PLP as a mediator of gene regulation in protein/amino acid nutrition.

Hepatic protein synthesis in suckling rats: effects of stage of development and fasting.

We studied the developmental changes in hepatic protein synthesis in suckling rats between postpartum d 1 and 28 and investigated the effect of fasting for 10 or 18 h on hepatic protein turnover at postpartum d 5, 10, 16, and 28. Fractional protein synthesis rates (KS, %/d) were measured in vivo using a flooding dose of L-[4-3H]phenylalanine. Although hepatic KS and translation efficiency (protein synthesis/unit RNA) were significantly higher at postpartum d 28 than d 1, the pattern of change was biphasic: KS and translational efficiency were higher at d 10 and 28 than at d 5 and 16. The largest increase in KS and translational efficiency occurred during the period normally associated with weaning (between postpartum d 16 and 28). At all stages of development, the KS and translational efficiency in fasted rats were significantly lower than those in control (fed) rats, although the relative decline in both measurements was largest at postpartum d 10. The absolute rates of hepatic protein synthesis declined to similar levels on d 5, 10, and 16 after 10 h of fasting and changed little after 18 h of fasting; this level was significantly higher at postpartum d 28. Our results suggest that postnatal development in suckling rats was marked by a biphasic pattern in the rates of hepatic protein synthesis, which increased during the neonatal and weaning periods. The relative changes in the synthesis and loss of hepatic protein in response to fasting were greater during the neonatal than during the late suckling and weaning periods.

Measurement of instant rates of protein degradation in the livers of intact mice by the accumulation of bestatin-induced peptides

Bestatin induces the accumulation of di- and tripeptide intermediates in cellular protein breakdown. In liver, a single set of bestatin-sensitive cytosolic peptidases are involved in the degradation to amino acids of the major classes of cellular proteins. Accumulation of bestatin-induced peptides, in isolated hepatocytes, is proportional to the rate of protein degradation (Botbol, V., and Scornik, O. A. (1989) J. Biol. Chem. 264, 13504-13509). Injection of 1 mg of bestatin into mice results in detectable amounts of hepatic intermediates in 15 min. We propose to use the accumulation of these peptides as a relative measurement of liver protein degradation. There is at present no other way to determine transient changes in protein breakdown in the tissues of intact animals. As an example of the applications of this procedure, we present the effects of a single meal on hepatic protein metabolism. Protein synthesis was estimated by the incorporation into liver protein of a massive dose of radioactive leucine (Scornik, O. A. (1974) J. Biol. Chem. 249, 3876-3883) and degradation of long-lived or short-lived proteins by the accumulation of bestatin-induced peptides, labeled in carboxy-C of their Leu or Arg moieties, 1 day or 1 h beforehand. A single meal resulted in an 18% increase in liver protein in 8 h, a 45% increase in the rate of hepatic protein synthesis, and a 3-fold decrease in the rate of breakdown of long-lived proteins. Short-lived proteins were not affected. To establish the efficiency with which bestatin-induced peptides accumulate in the livers of fasting mice, we compared them with the disappearance, in 1 day, of protein-bound 14C-guanidino-Arg residues, labeled by previous injection of 14C-bicarbonate (Swick, R. W., and Ip, M. M. (1974) J. Biol. Chem. 249, 6836-6841). From this comparison, we estimated that bestatin-induced Leu-labeled intermediates, accumulating in 15 min, represented 39% of the hepatic proteins degraded in that interval. For Arg-labeled intermediates the value was 55%. Correcting for these efficiencies, we estimate that in 4 h a meal decreased the rate of degradation of long-lived Arg-labeled proteins from 2.02 to 0.73%/h. For Leu-labeled proteins the estimated rates were 1.76 and 0.66%/h, respectively. Although a transient slowdown of liver protein degradation after a single meal had been suggested before, this is the first time that acute changes such as this can be determined directly in intact animals.(ABSTRACT TRUNCATED AT 400 WORDS)

Measurement of hepatic protein synthesis in unrestrained mice‐evaluation of the ‘flooding technique’

Controversy exists regarding the validity of various techniques for estimating rates of protein synthesis in vivo. In the present report, we have compared estimates of hepatic protein synthesis in normal mice with a pulse labelling of [1-14C]leucine and calculated hepatic protein synthetic rates in a conventional two-pool model and in a five-pool compartment analysis. Results obtained with pulse labelling were also compared to those obtained in animals receiving a flooding dose of 1.5 mumol L-phenylalanine and 0.4 microCi [U-14C]phenylalanine per gram of body weight or 1.0 mumol L-leucine and 0.4 microCi [l-14C]leucine per gram of body weight. Estimates of protein synthesis were calculated with plasma free amino acid, liver acid-soluble fraction and acylated tRNA specific radioactivities as being representative of the precursor pool for protein synthesis. Rates of hepatic protein synthesis obtained with pulse labelling and either leu-tRNA or acid-soluble fractions of liver leucine as the precursor for protein synthesis gave similar results (37 +/- 5 vs 42 +/- 5% per day) in a two-pool model, but disagreed in a five-pool model (37 +/- 5 vs 6 +/- 2% per day). Estimates based on plasma enrichment in leucine were only one fifth of values obtained with tRNA in labelling experiments. When the plasma pool with tracer amino acids was used to indicate the precursor labelling of protein synthesis, values obtained with the flooding dose of either phenylalanine or leucine agreed with those obtained with pulse labelling and enrichment in tRNA (30 +/- 3 nmol min-1 vs 28 +/- 4 nmol min-1); with however no agreement when the enrichment in the liver mixed tissue pool was used (76 +/- 5 nmol min-1). Complete equilibration of the amino acid pools did not occur despite flooding. Therefore, the flooding technique may only represent an approximate method to measure protein synthesis in vivo, although it gives absolute values that agree well with results from labelling techniques based on tRNA enrichment provided the plasma pool is used as the precursor enrichment.

Growth of the rat foetal liver in gestational diabetes

1. 1. Through a combination of streptozotocin and insulin injections an animal model of gestational diabetes has been established, whereby blood glucose concentrations are elevated over the second-half of pregnancy. 2. 2. Between 18 and 21 days of gestation the diabetic mothers carried smaller foetuses, which in turn possessed growth retarded livers. 3. 3. This suppression of hepatic growth in diabetic foetuses was evident in terms of consistently decreased (7–27%) liver weights and protein and nucleic acid contents. 4. 4. No differences were found between the rates of hepatic protein synthesis (measured in vivo) in control and diabetic foetuses. 5. 5. Hence, the growth retardation of the foetal liver, arising from maternal hyperglycaemia, must necessarily involve an increase in protein degradation.

Elevated Circulating Interleukin-6 Is Associated with an Acute-phase Response but Reduced Fixed Hepatic Protein Synthesis in Patients with Cancer

It has been suggested that, as part of the inflammatory response to the presence of a tumor, various cytokines are produced and these induce hepatic synthesis of acute-phase proteins (APP). Under these circumstances it is not known what changes occur in the fixed component of hepatic protein synthesis. The aim of this study was to compare circulating interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF) concentrations and fixed hepatic protein synthesis rates in a group of healthy controls (n = 6) with a group of patients with an established APP response secondary to hepatic metastasis from colorectal cancer (n = 6). Fixed hepatic protein synthesis rates were measured following a primed, constant 20-hour infusion of 15N-glycine. The liver was biopsied at laparotomy. The APP response was assessed by serum C-reactive protein concentration and cytokines were assayed by a combination of immunoassay and bioassay. The patients with advanced cancer and an on-going APP response had elevated circulating IL-6 concentrations (p less than 0.01). Rates of fixed hepatic protein synthesis were 30% lower than those observed in controls (p less than 0.01). These findings demonstrate that in patients with hepatic metastasis, although the synthesis of certain acute-phase export proteins can be increased, fixed protein synthesis is reduced. Whether these changes in the distribution of hepatic protein synthesis are mediated by IL-6 will require further investigation.

Amino Acid Metabolism in Human Cancer Cachexia

Cancer cachexia is a complex syndrome that occurs with variable incidence in patients with solid tumors and those with hematologic malignancies. It is associated with characteristic physical and laboratory findings, and at a more fundamental level, with significant abnormalities in carbohydrate, lipid, and protein metabolism. These alterations in intermediary metabolism are demonstrable early in the syndrome, even before the onset of weight loss, when the more characteristic features of cancer cachexia are evident. Progressive wasting of peripheral protein stores is a major feature of cancer cachexia and often one of the most graphic realities of malignancy for patients and their families. Unfortunately, significant problems with the animal models of cancer cachexia make conclusions derived from animal studies difficult to extrapolate to humans. Data from human studies indicate that human cancer cachexia is associated with minimal aberrations in circulating free amino acid concentrations; increased whole-body protein turnover, synthesis, and catabolism; reduced rates of skeletal muscle protein synthesis; and increased rates of hepatic protein synthesis. Whether or not these alterations represent pathologic responses or physiologic adaptation by the host to the presence of malignancy remains to be seen. Future investigations must focus on more careful evaluation of interorgan amino acid metabolism, investigation of skeletal muscle protein catabolic rates in cancer cachexia, and definition of the roles of altered hormonal and cytokine regulation of these processes. Such studies will more precisely define the level at which amino acid metabolism is altered significantly and, we hope, permit more specific therapeutic intervention designed to reverse the debilitating effects of cancer cachexia.

Influence of Preoperative Intravenous Nutrition upon Hepatic Protein Synthesis and Plasma Proteins and Amino Acids

The influence of 3 and 7 days of preoperative intravenous nutrition (IVN) on the capacity for protein synthesis in liver and on concentrations of plasma proteins and amino acids were investigated in patients with gastrointestinal malignancy. Thirty patients with gastrointestinal neoplasms who had lost more than 5 kg of weight over 3 months were randomized into three groups to receive preoperatively: (a) no IVN, (b) IVN for 3 days (0.18 gN/kg/day as amino acid; 30 kcal/kg/day as glucose), or (c) IVN for 7 days. Free access to a hospital diet was available to all patients including 10 patients who had not lost weight who served as controls. In the three groups of patients who had lost weight, median transferrin and fibronectin were lower than for controls, whereas other proteins and amino acids were comparable. After feeding, samples of liver were obtained peroperatively and the potential rates of protein synthesis were calculated from the in vitro incorporation of (14C)-leucine, into protein. Preoperative IVN significantly increased the potential rate of protein synthesis in liver after 3 days. Plasma amino acids were comparable with controls whereas in the unfed-group concentrations suggested utilization of alanine and breakdown of muscle. Three days of IVN also increased plasma fibronectin and IgA but increases of prealbumin, IgM, and complement C3 were only significant in the group fed for 7 days. On the 7th postoperative day plasma proteins were decreased similarly in each group. This study shows that concentrations of several plasma proteins, in preoperative patients reflect net rates of hepatic protein synthesis and are susceptible to depletion during starvation and repletion by 3 or 7 days of IVN.

AN INVESTIGATION INTO THE EFFECTS OF CHRONIC ETHANOL FEEDING ON HEPATIC MIXED PROTEIN SYNTHESIS IN IMMATURE AND MATURE RATS

1. The response of the liver to chronic ethanol feeding was investigated in sexually immature (85 g) and sexually mature (280 g) male Wistar rats. Rats received a nutritionally adequate liquid diet ad libitum, in which ethanol comprised 36% of total calories, for up to 6 weeks. Controls were pair-fed the same liquid diet in which ethanol was substituted by isocaloric glucose. 2. In immature rats, total hepatic protein, RNA and DNA contents were reduced by 12-23%. The amount of RNA, relative to protein or DNA, was also decreased by 11-12%, though the amount of protein relative to DNA was unaltered. In mature rats, no change in total hepatic protein and DNA contents were observed, though total RNA, RNA/protein ratio, RNA/DNA ratio and the amount of protein relative to DNA was reduced by 7-18%. 3. Rates of protein synthesis were measured with a flooding dose of L[4-3H]-phenylalanine without anaesthesia or surgical stress. In both immature and mature rats the fractional and absolute rates of hepatic protein synthesis and protein synthesis relative to DNA were reduced by approx 25%.

Regulation of hepatic acute phase protein synthesis by products of interleukin 2 (IL 2)-stimulated human peripheral blood mononuclear cells.

Cancer patients injected with recombinant human IL 2 develop marked changes in serum concentrations of hepatic acute-phase proteins. To determine if this acute-phase response involves a change in the rate of hepatic protein synthesis and if it is due to a direct effect of IL 2 on hepatocytes, human hepatoma-derived hepatocytes (Hep-3B cells) were incubated in medium containing IL 2 or in culture supernatants from IL 2-activated human peripheral blood mononuclear cells (PBMNC). The rate of synthesis of two acute-phase proteins, complement protein factor B and albumin, was determined by the incorporation of a radiolabeled amino acid precursor into newly synthesized protein as measured by analytical gel electrophoresis of immunoprecipitates. IL 2 in concentrations from 1 to 1000 U/ml had no effect on the synthesis of factor B or albumin; conversely, there was a dose-dependent increase in the rate of synthesis of factor B and decrease in albumin synthesis mediated by culture supernatants of IL 2-activated PBMNC. The magnitude of the effect of acute-phase protein synthesis was dependent on the IL 2 concentration used for the activation of PBMNC. The rate of factor B synthesis increased approximately 4.0-fold in the presence of culture supernatants of PBMNC activated with either opsonized heat-killed Staphylococcus albus or with 1000 U/ml IL 2. Preincubation of the IL 2-activated PBMNC culture supernatants with an antiserum specific for recombinant IL 1-beta completely neutralized the capacity of the supernatants to stimulate factor B synthesis, whereas antisera specific for human IL 1-alpha or for tumor necrosis factor had no effect. These results indicate that the indirect effect of IL 2 on hepatic acute phase protein synthesis is mediated by IL 1-beta.

Effect of long-term ethanol intake on the content of selenium in rat liver: relation to the rate of hepatic protein synthesis.

Effect of long-term ethanol intake on the content of selenium in rat liver: relation to the rate of hepatic protein synthesis.