Hepatic Protein Synthesis Research Articles

Roles of FGFs As Paracrine or Endocrine Signals in Liver Development, Health, and Disease.

The liver plays important roles in multiple processes including metabolism, the immune system, and detoxification and also has a unique capacity for regeneration. FGFs are growth factors that have diverse functions in development, health, and disease. The FGF family now comprises 22 members. Several FGFs have been shown to play roles as paracrine signals in liver development, health, and disease. FGF8 and FGF10 are involved in embryonic liver development, FGF7 and FGF9 in repair in response to liver injury, and FGF5, FGF8, FGF9, FGF17, and FGF18 in the development and progression of hepatocellular carcinoma. In contrast, FGF15/19 and FGF21 are endocrine signals. FGF15/19, which is produced in the ileum, is a negative regulator of bile acid metabolism and a stimulator of gallbladder filling. FGF15/19 is a postprandial, insulin-independent activator of hepatic protein and glycogen synthesis. It is also required for hepatocellular carcinoma and liver regeneration. FGF21 is a hepatokine produced in the liver. FGF21 regulates glucose and lipid metabolism in white adipose tissue. Serum FGF21 levels are elevated in non-alcoholic fatty liver. FGF21 also protects against non-alcoholic fatty liver. These findings provide new insights into the roles of FGFs in the liver and potential therapeutic strategies for hepatic disorders.

Frequency and Pathophysiology of Acute Liver Failure in Ornithine Transcarbamylase Deficiency (OTCD).

BackgroundAcute liver failure (ALF) has been reported in ornithine transcarbamylase deficiency (OTCD) and other urea cycle disorders (UCD). The frequency of ALF in OTCD is not well-defined and the pathogenesis is not known.AimTo evaluate the prevalence of ALF in OTCD, we analyzed the Swiss patient cohort. Laboratory data from 37 individuals, 27 females and 10 males, diagnosed between 12/1991 and 03/2015, were reviewed for evidence of ALF. In parallel, we performed cell culture studies using human primary hepatocytes from a single patient treated with ammonium chloride in order to investigate the inhibitory potential of ammonia on hepatic protein synthesis.ResultsMore than 50% of Swiss patients with OTCD had liver involvement with ALF at least once in the course of disease. Elevated levels of ammonia often correlated with (laboratory) coagulopathy as reflected by increased values for international normalized ratio (INR) and low levels of hepatic coagulation factors which did not respond to vitamin K. In contrast, liver transaminases remained normal in several cases despite massive hyperammonemia and liver involvement as assessed by pathological INR values. In our in vitro studies, treatment of human primary hepatocytes with ammonium chloride for 48 hours resulted in a reduction of albumin synthesis and secretion by approximately 40%.ConclusionIn conclusion, ALF is a common complication of OTCD, which may not always lead to severe symptoms and may therefore be underdiagnosed. Cell culture experiments suggest an ammonia-induced inhibition of hepatic protein synthesis, thus providing a possible pathophysiological explanation for hyperammonemia-associated ALF.

Hepatoprotective Effect of Wheat-Based Solid-State Fermented Antrodia cinnamomea in Carbon Tetrachloride-Induced Liver Injury in Rat.

Antrodia cinnamomea (A. cinnamomea) is an indigenous medical fungus in Taiwan and has multiple biological functions, including hepatoprotective and immune-modulatory effects. Currently, the commercially available A. cinnamomea are mainly liquid- and solid-state fermented A. cinnamomea. However, the hepatoprotective effect of solid-state fermented A. cinnamomea has never been reported. Here we evaluate the ability of air-dried, ground and non-extracted wheat-based solid-state fermented A. cinnamomea (WFAC) to protect against carbon tetrachloride (CCl4)-induced hepatic injury in vivo. The results showed that oral administration of WFAC dose dependently (180, 540 and 1080 mg/kg) ameliorated the increase in plasma aspartate aminotransferase and alanine aminotransferase levels caused by chronic repeated CCl4 intoxication in rats. WFAC significantly reduced the CCl4-induced increase in hepatic lipid peroxidation levels and hydroxyproline contents, as well as reducing the spleen weight and water content of the liver. WFAC also restored the hepatic soluble protein synthesis and plasma albumin concentration in CCl4-intoxicated rats, but it did not affect the activities of superoxide dismutase, catalase, or glutathione peroxidase. In addition, a hepatic morphological analysis showed that the hepatic fibrosis and necrosis induced by CCl4 were significantly ameliorated by WFAC. Furthermore, the body weights of control rats and WFAC-administered rats were not significantly different, and no adverse effects were observed in WFAC-administered rats. These results indicate that WFAC is a nontoxic hepatoprotective agent against chronic CCl4-induced hepatic injury.

The Increase in Liver Polyamine Concentration Contributes to the Tryptophan‐induced Stimulation of Hepatic Protein Synthesis

Tryptophan has a unique role as a nutritional signaling molecule that regulates protein synthesis in mice and rat liver. However, the mechanism of the stimulating actions of tryptophan on hepatic protein synthesis has not been clearly elucidated. Tryptophan has been suggested to stimulate protein synthesis at the translational level, because polysome aggregation was observed in a short time after oral administration of tryptophan. Therefore, we focused on the acute effects of tryptophan on protein synthesis. In the present study, proteomic and metabolomic analysis was performed to identify candidate proteins and metabolites, which are likely to play a role in stimulation of protein synthesis by tryptophan. Eighteen hours fasted Wistar rats were divided into 3 groups. One group of animals was sacrificed without any treatment as a control. Remaining two groups of animals were administered 135mg/100g body weight L‐tryptophan by oral gavage and then sacrificed after 1h or 3h after administration. With two‐dimensional electrophoresis and image analysis, four differentially expressed protein spots were detected at 3h after administration of tryptophan, and one of which was identified as key enzyme in the biosynthetic pathway of ornithine, ornithine aminotransferase (OAT) precursor. OAT is the main catabolic enzyme of ornithine and its expression was significantly decreased by tryptophan administration. The concentration of ornithine was increased in both serum and liver at 3h after administration of tryptophan. Ornithine is a precursor for polyamine biosynthesis. Ornithine decarboxylase (ODC) catalyzes the first step in the polyamine biosynthetic pathway forming putrescine, which is then converted into the polyamines spermidine and spermine. It has been reported that oral administration of tryptophan to overnight‐fasted rats exhibited increase in the hepatic ODC activity. Significantly increased concentrations of polyamines, as well as ornithine were found in the liver at 3h after administration of tryptophan. Based on these results, we speculate that the increase in ornithine level through suppression of OAT expression and stimulation of ODC activity by tryptophan administration may lead to accelerated polyamine synthesis and thereby promote protein synthesis in the liver.

Syndrome d’activation macrophagique sous tocilizumab : mythe ou réalité ?

IntroductionSome authors have reported macrophage activation syndrome (MAS) secondary to infusion of tocilizumab, a monoclonal antibody that blocks interleukin-6 (IL-6). The pathophysiology of MAS is however linked to uncontrolled activation of innate immunity, mediated in part by IL-6. We conducted a study for macrophage activation biomarkers in a cohort of patients treated with tocilizumab. ResultsTwenty-seven patients were included prospectively in our center. Levels of neutrophils, platelets, CRP and fibrinogen were lower at the end of treatment than at initiation (P<0.05); other biomarkers were stable. There was neither clinical sign of SAM nor hemophagocytosis in myelogram. ConclusionLaboratory abnormalities are related to direct blockade of IL-6 by tocilizumab and decrease hepatic protein synthesis. Tocilizumab is not responsible for MAS and associations described are more likely to be related to the autoimmune underlying disease, rather than treatment.

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.

Anti-interleukin-6 therapy through application of a monogenic protein inhibitor via gene delivery.

Anti-cytokine therapies have substantially improved the treatment of inflammatory and autoimmune diseases. Cytokine-targeting drugs are usually biologics such as antibodies or other engineered proteins. Production of biologics, however, is complex and intricate and therefore expensive which might limit therapeutic application. To overcome this limitation we developed a strategy that involves the design of an optimized, monogenic cytokine inhibitor and the protein producing capacity of the host. Here, we engineered and characterized a receptor fusion protein, mIL-6-RFP-Fc, for the inhibition of interleukin-6 (IL-6), a well-established target in anti-cytokine therapy. Upon application in mice mIL-6-RFP-Fc inhibited IL-6-induced activation of the transcription factor STAT3 and ERK1/2 kinases in liver and kidney. mIL-6-RFP-Fc is encoded by a single gene and therefore most relevant for gene transfer approaches. Gene transfer through hydrodynamic plasmid delivery in mice resulted in hepatic production and secretion of mIL-6-RFP-Fc into the blood in considerable amounts, blocked hepatic acute phase protein synthesis and improved kidney function in an ischemia and reperfusion injury model. Our study establishes receptor fusion proteins as promising agents in anti-cytokine therapies through gene therapeutic approaches for future targeted and cost-effective treatments. The strategy described here is applicable for many cytokines involved in inflammatory and other diseases.

L-Asparaginase lowers plasma antithrombin and mannan-binding-lectin levels: Impact on thrombotic and infectious events in children with acute lymphoblastic leukemia.

L-asparaginase, a key therapeutic agent in the management of patients with acute lymphoblastic leukemia (ALL), dramatically impairs hepatic protein synthesis. We investigated the effects of prolonged exposure to L-asparaginase on antithrombin (AT), fibrinogen and mannan-binding-lectin (MBL) levels, and on the occurrence of thrombotic events (TE) and febrile neutropenia episodes (FN) in pediatric patients. Protein levels were measured in 97 children during 30 weeks of chemotherapy with L-asparaginase and up to 1 year following remission. TE and FN episodes were recorded during this period. Median AT level decreased from 0.96 IU/mL prior to treatment (range: 0.69-1.38) to 0.55 IU/mL (0.37-0.76) during therapy. Fibrinogen and MBL decreased from 3.18 g/L (1.29-7.28) and 1,177 ng/mL (57-5,343) to 1.56 g/L (0.84-2.13) and 193 ng/mL (57-544), respectively. All three proteins had recovered 1-4 weeks after L-asparaginase cessation. TE were reported in 22 (23%) patients. Of these, 11 occurred after a median of 10 administrations of L-asparaginase. Fifty-one FN were associated with infections, of which 36 occurred during treatment with L-asparaginase. Patients with low levels of MBL at diagnosis were at higher risk of FN associated with infections (RR = 1.59, 95%CI: 1.026-2.474). Both AT and MBL decreases were moderately correlated with fibrinogen (r = 0.51 and 0.58, respectively). Children with ALL are exposed to significant decrease in AT, fibrinogen and MBL levels, and concomitant increased risk of thrombosis and FN with infection during L-asparaginase treatment. Measuring plasma levels of these liver-derived proteins could help predict the occurrence of adverse events.

Venous thromboembolism in patients with liver diseases.

Chronicliverdiseases(CLD)arecharacterized bydecreased levels of most procoagulant factors and thrombocytopenia, leading to the assumption that they are a prototype of an acquired bleeding disorder. Indeed, decreased levels of procoagulant proteins are accompanied by impaired hepatic synthesis of the main natural anticoagulant proteins (antithrombin and protein C); in contrast, factor VIII levels are significantly increased. Finally, reduced levels of inhibitors of fibrinolysis are, at least in part, balanced by reduced

Continual feeding of two types of microalgal biomass affected protein digestion and metabolism in laying hens.

A 14-wk study was conducted to determine the nutritional efficacy and ssmetabolic impact of 2 types of microalgal biomass as alternative protein sources in laying hen diets. Shaver hens (total = 150 and 26 wk old) were fed 1 of 5 diets: a control or a defatted green microalgal biomass (DG; Desmodesmus spp.) at 25% and a full-fatted diatom biomass (FD; Staurosira spp.) at 11.7% inclusion with or without protease. This experiment consisted of 5 replicates per treatment and each replicate contained 6 hens individually reared in cages (1 hen for biochemical data/replicate). Despite decreased ADFI (P = 0.03), hens fed DG or FD had final BW, overall hen-day egg production, and egg quality similar to the controls. Feeding DG or FD did not alter plasma concentrations of insulin, glutamine, and uric acid or alkaline phosphatase activity at wk 8 or 14 but decreased plasma 3-methyhistine concentrations (P = 0.03) and tartrate-resistant acid phosphatase (TRAP) activities (P < 0.001) at wk 14 and improved (P = 0.002) ileal total AA digestibility. Although DG or FD exhibited moderate effects on intestinal brush border protease activities and mRNA levels of duodenal transporters Pept1, Lat1, and Cat1, both substantially enhanced (P < 0.05) phosphorylation of hepatic protein synthesis key regulator S6 ribosomal protein (S6) and the ratio of phospho-S6 to S6 in the liver of hens. However, DG and FD manifested with different impacts on weights of egg and egg albumen, proteolytic activity of jejunal digesta, plasma TRAP activity, ileal total AA digestibility, and several intestinal genes and hepatic proteins. Supplemental protease in the DG and FD diets produced mixed effects on a number of measures. In conclusion, our findings revealed the feasibility of including greater levels of microalgal biomass as a source of feed protein for laying hens and a novel potential of the biomass in improving dietary protein digestion and body protein metabolism than previously perceived.

Disruption of genes encoding eIF4E binding proteins-1 and -2 does not alter basal or sepsis-induced changes in skeletal muscle protein synthesis in male or female mice.

Sepsis decreases skeletal muscle protein synthesis in part by impairing mTOR activity and the subsequent phosphorylation of 4E-BP1 and S6K1 thereby controlling translation initiation; however, the relative importance of changes in these two downstream substrates is unknown. The role of 4E-BP1 (and -BP2) in regulating muscle protein synthesis was assessed in wild-type (WT) and 4E-BP1/BP2 double knockout (DKO) male mice under basal conditions and in response to sepsis. At 12 months of age, body weight, lean body mass and energy expenditure did not differ between WT and DKO mice. Moreover, in vivo rates of protein synthesis in gastrocnemius, heart and liver did not differ between DKO and WT mice. Sepsis decreased skeletal muscle protein synthesis and S6K1 phosphorylation in WT and DKO male mice to a similar extent. Sepsis only decreased 4E-BP1 phosphorylation in WT mice as no 4E-BP1/BP2 protein was detected in muscle from DKO mice. Sepsis decreased the binding of eIF4G to eIF4E in WT mice; however, eIF4E•eIF4G binding was not altered in DKO mice under either basal or septic conditions. A comparable sepsis-induced increase in eIF4B phosphorylation was seen in both WT and DKO mice. eEF2 phosphorylation was similarly increased in muscle from WT septic mice and both control and septic DKO mice, compared to WT control values. The sepsis-induced increase in muscle MuRF1 and atrogin-1 (markers of proteolysis) as well as TNFα and IL-6 (inflammatory cytokines) mRNA was greater in DKO than WT mice. The sepsis-induced decrease in myocardial and hepatic protein synthesis did not differ between WT and DKO mice. These data suggest overall basal protein balance and synthesis is maintained in muscle of mice lacking both 4E-BP1/BP2 and that sepsis-induced changes in mTOR signaling may be mediated by a down-stream mechanism independent of 4E-BP1 phosphorylation and eIF4E•eIF4G binding.

Acute phase proteins and their use in the diagnosis of diseases in ruminants: a review

The acute phase response is a complex systemic early-defence system of reactions activated by trauma, infection, tissue damage, inflammation, stress or neoplasia. One of the most important elements of this response is the increased hepatic synthesis of some plasma proteins, collectively known as acute phase proteins. The discovery of these new biomarkers has allowed the clinical monitoring of different diseases; therefore, their clinical application has been studied widely in human medicine in order to improve the diagnosis, evaluation, treatment, prognosis and therapeutics of many diseases. Although a wide range of studies have been carried out to determine the usefulness of acute phase proteins in several diseases also in animals, they are still relatively under-utilised in veterinary medicine, predominantly in farm animals. The acute phase response and clinical application of acute phase proteins in ruminants are reviewed in this article, including their diagnostic use in clinical practice and application in the monitoring of treatment, which is one of the most promising practical uses of these proteins. &amp;nbsp;

EComment. Is the maintenance of haemostasis possible without fibrinogen?

Although fibrinogen is a key factor in thrombosis, its role in the pathogenesis of haemostatic disturbances after cardiac surgery is often underestimated. Therefore we were glad to read the article by Gielen et al. [1]. Apparently during the postoperative period, decrease in fibrinogen often coincides with the deficiency of other clotting factors and platelet dysfunction, and the level of postoperative blood loss does not depend only on the fibrinogen concentration. Thus, there are no linear connections between blood loss and the level of fibrinogen. However, we cannot underestimate the contribution of this clotting factor in the mechanical stability of clots, which also depends on platelets, coagulation factor XIII and von Willebrand factor. The deficiency of those factors, primarily fibrinogen, leads to the decrease in the fibrin monomer and its polymerization, which further results in delayed thrombus formation along with increase of fibrinolysis sensitivity and blood loss. Based on thromboelastography data, a feedback loop exists between the fibrinogen level and maximum lysis [2]. Therefore, the fibrinogen level serves as an integral value of the formation and stabilization of the clot. It is necessary to note that the velocity of fibrin formation may be affected by the absolute quantity of fibrinogen and its concentration, therefore hypofibrinogenaemia may be the result either of fibrinogen loss or haemodilution. The main target of haemodilution is the formation and stability of the clot, but not the thrombin formation [3]. We tested the connection between pre- and postoperative coagulation values and the level of blood loss after cardiac surgical procedures in children. For patients with congenital heart disease, we consider a threshold fibrinogen concentration of 2.5 g/l to be necessary for prevention of bleeding. In cases with lower concentrations of fibrinogen, we observed postoperative blood losses of 0.75 ml/kg/h to 1.27 ml/kg/h [4]. Hypofibrinogenaemia in children may be caused by hypotrophy due to social (early artificial feeding) and medical factors, impaired hepatic protein synthesis, and a decrease in terminal elimination half-life in cyanotic patients. A postoperative level of fibrinogen less than 2 g/l led to blood loss of 0.61 to 0.85 ml/kg/h [2]. Indeed, there is insufficient evidence to prove that the use of fibrinogen concentrate after cardiac surgery is successful. However, a controlled replacement therapy of blood loss via the use of fibrinogen concentrate in hypofibrinogenaemia is efficient and abolishes the deficiency of other haemostasis components without the risk of thrombosis development. On the other hand, based on stoichiometry, a possible way to circumvent a low level of fibrinogen concentration may be the optimization of the circulating blood volume via the application of ultrafiltration. Conflict of interest: none declared

Prophylaxis of hepatic insufficiency after major hepatic resections

The article deals with a problem of prophylaxis of hepatic insufficiency in oncological patients after liver resections. We analyzed data of effectiveness and safety of the use of Remaxol in oncological patients with hepatic metastasis of colorectal cancer--dynamics of indicators of cytolysis and cholestasis, hepatic protein synthesis, exchange of pigments, pro- and antioxidant system and the level of endogen intoxication in postoperative period. Use of Remaxol allows decreasing the duration of postoperative rehabilitation and intensive care unit staying.

Low molecular weight heparin in portal vein thrombosis of cirrhotic patients: only therapeutic purposes?

Cirrhosis has always been regarded as hemorrhagic coagulopathy caused by the reduction in the hepatic synthesis of procoagulant proteins. However, with the progression of liver disease, the cirrhotic patient undergoes a high rate of thrombotic phenomena in the portal venous system. Although the progression of liver failure produces a reduction in the synthesis of anticoagulant molecules, a test able to detect the patients with hemostatic balance shifting towards hypercoagulability has not yet been elaborated. The need of treatment and/or prophylaxis of cirrhotic patients is demonstrated by the increased mortality, the risk of bleeding from esophageal varices, and the mortality of liver transplantation, when portal vein thrombosis (PVT) occurs even if current guidelines do not give indications about PVT treatment in cirrhosis. In view of the general feeling that the majority of cirrhotic patients at an advanced stage may be in a procoagulant condition (suggested by the sharp increase in the prevalence of PVT), it is presumable that a prophylaxis of this population could be of benefit. The safety and the efficacy of prophylaxis and treatment with enoxaparin in patients with cirrhosis demonstrated by a single paper suggest this option only in controlled trials and, currently, there are no sufficient evidences for a recommendation in the clinical practice.

Enteral Arginine Partially Ameliorates Parenteral Nutrition–Induced Small Intestinal Atrophy and Stimulates Hepatic Protein Synthesis in Neonatal Piglets

Arginine is an indispensable amino acid in neonates; de novo synthesis of arginine occurs in the small intestine (SI) but is reduced during parenteral nutrition (PN), limiting the arginine available to the mucosa. We assessed the effects of route of intake and dietary concentration of arginine on protein synthesis, superior mesenteric artery (SMA) blood flow, and SI morphology. Piglets (n = 18, 14-17 days old) were given complete PN for 3 days to induce SI atrophy, then switched to 1 of 3 treatments: arginine-free PN plus an intragastric (IG) infusion of high arginine (1.6 g · kg(-1)· d(-1), IG-H Arg) or low arginine (0.6 g · kg(-1)· d(-1), IG-L Arg) or complete high-arginine PN (1.6 g · kg(-1)· d(-1), IV-H Arg). Enteral arginine, irrespective of amount provided, stimulated hepatic protein synthesis compared with intravenous delivery of arginine (P = .01). SMA blood flow declined for all groups following the initiation of PN. After 48 hours on the test diets, all groups reached low constant levels, but the IV-H group was significantly higher than both IG groups (P < .05). Despite greater blood flow, the SI morphological characteristics in IV-H Arg pigs were not significantly improved over the other groups. IV-H Arg pigs had higher plasma concentrations of indispensable amino acids (tyrosine, isoleucine, and valine) compared with IG-H Arg, despite identical amino acid intakes. Intravenous delivery of arginine sustained the best SMA blood flow, whereas even a moderate amount of enteral arginine stimulated liver protein synthesis and maintained SI growth, independent of blood flow.

Role for cytoplasmic nucleotide hydrolysis in hepatic function and protein synthesis

Nucleotide hydrolysis is essential for many aspects of cellular function. In the case of 3',5'-bisphosphorylated nucleotides, mammals possess two related 3'-nucleotidases, Golgi-resident 3'-phosphoadenosine 5'-phosphate (PAP) phosphatase (gPAPP) and Bisphosphate 3'-nucleotidase 1 (Bpnt1). gPAPP and Bpnt1 localize to distinct subcellular compartments and are members of a conserved family of metal-dependent lithium-sensitive enzymes. Although recent studies have demonstrated the importance of gPAPP for proper skeletal development in mice and humans, the role of Bpnt1 in mammals remains largely unknown. Here we report that mice deficient for Bpnt1 do not exhibit skeletal defects but instead develop severe liver pathologies, including hypoproteinemia, hepatocellular damage, and in severe cases, frank whole-body edema and death. Accompanying these phenotypes, we observed tissue-specific elevations of the substrate PAP, up to 50-fold in liver, repressed translation, and aberrant nucleolar architecture. Remarkably, the phenotypes of the Bpnt1 knockout are rescued by generating a double mutant mouse deficient for both PAP synthesis and hydrolysis, consistent with a mechanism in which PAP accumulation is toxic to tissue function independent of sulfation. Overall, our study defines a role for Bpnt1 in mammalian physiology and provides mechanistic insights into the importance of sulfur assimilation and cytoplasmic PAP hydrolysis to normal liver function.

Reciprocal antagonism between inflammation and the protein C system

Protein C is a vitamin K-dependent serine protease secreted by the hepatocytes as an inactive zymogen and activated by thrombin bound to endothelial thrombomodulin. An endothelial protein C receptor (EPCR) is involved in both activation and enhancement of protein C activity, resulting in proteolytic degradation of clotting factors Va and VIIIa, thereby providing an efficient anticoagulant mechanism. Evidence was also provided that proinflammatory cytokines would impair the endothelia-mediated activation and activity of the Protein C system by inducing an internalization and proteolytic degradation of thrombomodulin and by shedding EPCR from the surface of endothelial cells membrane. Clinical and experimental studies also emphasized that an inflammatory acute phase reaction is accompanied by a commuted hepatic protein synthesis leading to an increase of plasma fibrinogen, factor VIII:C and of α1 protease inhibitor, while the plasma level of protein C zymogen decrease. On the other hand infusions of activated protein C were reported to protect from a toxico-septic shock by exerting not only anticoagulant but also anti-inflammatory effects.

Acquired Liver Injury in the Intensive Care Unit

HE liver plays a key role in the synthesis of proteins, metabolism of toxins and drugs, and in modulation of immunity. In critically ill patients, hypoxic, toxic, and inflammatory insults can affect hepatic excretory, synthetic, and/or purification functions, leading to systemic complications such as coagulopathy, increased risk of infection, hypoglycemia, and acute kidney injury. In severe cases, hepatic encephalopathyorbraindysfunction(acuteliverfailure)may occur. Because of the lack of specificity of standard laboratory investigations, identifying liver injury or dysfunction in critically ill patients remains a significant challenge. In addition, the great heterogeneity of criteria used to define the consequences of liver insults increases the difficulties for the clinician to properly interpret hepatic biochemical abnormalities. In this review, we choose to defineliver injuryas an elevation in serum concentrations of routinely measured hepatic enzymes, including aminotransferases (aspartate aminotransferase [AST]; alanine aminotransferase, [ALT]), alkaline phosphatase (ALP), or!-glutamyl transpeptidase. Hepatic dysfunctionrefers to derangement of pathways related to synthetic or clearance function, including international normalized ratio (INR) and bilirubin.Hepatotoxicity refers to hepatic injury and dysfunction caused by a drug or another noninfectious agent. 1 Acute liver failuredesignates

Portal glucose delivery stimulates muscle but not liver protein metabolism

Portal vein glucose delivery (the portal glucose signal) stimulates glucose uptake and glycogen storage by the liver, whereas portal amino acid (AA) delivery (the portal AA signal) induces an increase in protein synthesis by the liver. During a meal, both signals coexist and may interact. In this study, we compared the protein synthesis rates in the liver and muscle in response to portal or peripheral glucose infusion during intraportal infusion of a complete AA mixture. Dogs were surgically prepared with hepatic sampling catheters and flow probes. After a 42-h fast, they underwent a 3-h hyperinsulinemic (4× basal) hyperglucagonemic (3× basal) hyperglycemic (≈160 mg/dl) hyperaminoacidemic (hepatic load 1.5× basal; delivered intraportally) clamp (postprandial conditions). Glucose was infused either via a peripheral (PeG; n = 7) or the portal vein (PoG; n = 8). Protein synthesis was assessed with a primed, continuous [(14)C]leucine infusion. Net hepatic glucose uptake was stimulated by portal glucose infusion (+1 mg·kg(-1)·min(-1), P < 0.05) as expected, but hepatic fractional AA extraction and hepatic protein synthesis did not differ between groups. There was a lower arterial AA concentration in the PoG group (-19%, P < 0.05) and a significant stimulation (+30%) of muscle protein synthesis associated with increased expression of LAT1 and ASCT2 AA transporters and p70S6 phosphorylation. Concomitant portal glucose and AA delivery enhances skeletal muscle protein synthesis compared with peripheral glucose and portal AA delivery. These data suggest that enteral nutrition support may have an advantage over parenteral nutrition in stimulating muscle protein synthesis.