Biomedical subjects

K Jungermann

Publications and source records attributed to K Jungermann.

At least 55 records · Page 3Linked to original sources

PubMed1997

Purification of a RNA-binding protein from rat liver. Identification as ferritin L chain and determination of the RNA/protein binding characteristics.

In cultured rat hepatocytes the degradation of phosphoenolpyruvate carboxykinase mRNA might be regulated by protein(s), which by binding to the mRNA alter its stability. The 3'-untranslated region of phosphoenolpyruvate carboxykinase mRNA as a potential target was used to select RNA-binding protein(s) from rat liver by the use of gel retardation assays. A cytosolic protein was isolated, which bound to the phosphoenolpyruvate carboxykinase mRNA 3'-untranslated region and other in vitro synthesized RNAs. The protein was purified to homogeneity; it had an apparent molecular mass of 400 kDa and consisted of identical subunits with an apparent size of 24.5 kDa. Sequence analysis of a tryptic peptide from the 24.5-kDa protein revealed its identity with rat ferritin light chain. Binding of ferritin to RNA was abolished after phosphorylation with cAMP-dependent protein kinase and was augmented after dephosphorylation with alkaline phosphatase. Weak binding was observed in extracts from okadaic acid-treated cultured hepatocytes compared with untreated cells. Preincubation of ferritin with an anti-phosphoserine or an anti-phosphothreonine antibody attenuated binding to RNA, while an anti-phosphotyrosine antibody generated a supershift indicating that phosphoserine and phosphothreonine but not phosphotyrosine residues were in close proximity to the RNA-binding region. Ferritin is the iron storage protein in the liver. Binding of ferritin to RNA was diminished in the presence of increasing iron concentrations, whereas the iron chelator desferal was without effect. It is concluded that ferritin might function as RNA-binding protein and that it may have important functions in the general regulation of cellular RNA metabolism.

Animals↗

PubMed1997

A new role for enteric glucagon-37: acute stimulation of glucose absorption in rat small intestine.

Glucagon-37 is secreted by intestinal L-cells following carbohydrate uptake. It is known to inhibit gastric acid secretion (hence also named oxyntomodulin) and appears to increase intracellular cyclic AMP concentrations. Since cyclic AMP could enhance intestinal glucose absorption, a possible stimulatory effect of glucagon-37 on glucose transport was examined. Glucagon-37 acutely increased glucose absorption in the isolated, vascularly perfused small intestine and in isolated enterocytes of the rat. In these cells the stimulation by glucagon-37 could be completely blocked by the cAMP antagonist Rp-cAMPS and was therefore mediated by cAMP. The stimulation of intestinal glucose absorption by glucagon-37 appears to be a major new physiological function.

Animals↗

PubMed1997

Anaphylatoxin C5a receptor mRNA is strongly expressed in Kupffer and stellate cells and weakly in sinusoidal endothelial cells but not in hepatocytes of normal rat liver.

Anaphylatoxins (C5a and C3a), which are generated during complement activation, have recently been shown to increase glucose output from hepatocytes (HC) in perfused rat liver. They did not act directly on HC but indirectly by prostanoid release from non-parenchymal cells (NPC), probably Kupffer cells (KC). In order to corroborate this mechanism, the distribution of anaphylatoxin receptors in the different cell types of rat liver was determined by quantitative RT-PCR with primers specific for the rat C5a receptor (rC5aR) using RNA isolated from KC, sinusoidal endothelial cells (SEC), hepatic stellate cells (HSC) and HC. In line with functional data, C5aR mRNA was detected in freshly isolated NPC but not in HC of rat liver. Mainly KC but also HSC clearly expressed C5aR mRNA, while SEC did so only weakly. KC expressed up to 10-fold more C5aR mRNA than HSC and these in turn up to 10-fold more than SEC. These results support the proposed indirect action of anaphylatoxins on HC.

Animals↗

PubMed1997

Sensing by intrahepatic muscarinic nerves of a portal-arterial glucose concentration gradient as a signal for insulin-dependent glucose uptake in the perfused rat liver.

In vivo, insulin increases net hepatic glucose uptake efficiently only in the presence of a portal-arterial glucose gradient. In isolated perfused rat livers supplied with a glucose gradient (portal 10 mM/arterial 5 mM) insulin-induced glucose uptake was blocked by atropine; in livers not supplied with the gradient (portal = arterial 5 mM) insulin-dependent glucose uptake was elicited by acetylcholine. Apparently, the gradient was sensed and transformed into a metabolic signal by intrahepatic nerves, releasing acetylcholine to muscarinic receptors.

Animals↗

PubMed1997

The C-terminal domain of the Gs-coupled EP4 receptor confers agonist-dependent coupling control to Gi but no coupling to Gs in a receptor hybrid with the Gi-coupled EP3 receptor.

Prostaglandin E2 receptors (EPR) belong to the family of G-protein-coupled receptors with 7 transmembrane domains. They form a family of four subtypes, which are linked to different G-proteins. EP1R are coupled to Gq, EP2 and EP4R to Gs and EP3R to Gi. Different C-terminal splice variants of the bovine EP3R are coupled to different G-proteins. A mouse EP3R whose C-terminal domain had been partially truncated no longer showed agonist-induced Gi-protein activation and was constitutively active. In order to test the hypothesis that the C-terminal domain confers coupling specificity of the receptors on the respective G-proteins, a cDNA for a hybrid rEP3hEP4R, containing the N-terminal main portion of the Gi-coupled rat EP(3beta)R including the 7th transmembrane domain and the intracellular C-terminal domain of the Gs-coupled human EP4R, was generated by PCR. HEK293 cells transiently transfected with the chimeric rEP3hEP4R cDNA expressed a plasma membrane PGE2 binding site with a slightly lower Kd value for PGE2 but an identical binding profile for receptor-specific ligands as cells transfected with the native rat EP(3beta)R. In HepG2 cells stably transfected with the chimeric rEP3hEP4R cDNA PGE2 did not increase cAMP formation characteristic of Gs coupling but attenuated the forskolin-stimulated cAMP synthesis characteristic of Gi coupling. This effect was inhibited by pre-treatment of the cells with pertussis toxin. Thus, the hybrid receptor behaved both in binding and in functional coupling characteristics as the native rat EP(3beta)R. Apparently, the intracellular C-terminal domain did not confer coupling specificity but coupling control, i.e. allowed a signalling state of the receptor only with agonist binding.

Animals↗

PubMed1997

Arterial oxygen partial pressures reduce the insulin-dependent induction of the perivenously located glucokinase in rat hepatocyte cultures: mimicry of arterial oxygen pressures by H2O2.

Liver glucokinase (GK) is localized predominantly in the perivenous zone. GK mRNA was induced by insulin maximally under venous O2 partial pressure (pO2) and only half-maximally under arterial pO2. CoCl2 and desferrioxamine mimicked venous pO2 and enhanced the insulin-dependent induction of GK mRNA under arterial pO2. H2O2 mimicked arterial pO2 and reduced insulin-induced GK mRNA under venous pO2 to the lower arterial levels. Thus the zonal O2 gradient in liver seems to have a key role in the heterogenous expression of the GK gene.

Animals↗

PubMed1997

Impairment of metabolic hepatic nerve action by chronic but not acute ethanol intoxication studied in isolated perfused rat liver.

BACKGROUND/AIMS: Liver carbohydrate metabolism and blood flow are regulated by hepatic nerves and hormones such as glucagon, insulin or catecholamines. Acute and chronic application of alcohol are known to depress the function of central and peripheral nerves. The extent of inhibition of the autonomic nervous system is not well characterized; thus, the possible impairment of hepatic nerve function by acute and chronic application of ethanol was investigated. METHODS: Rat livers were perfused simultaneously via both the portal vein and hepatic artery. Hepatic nerves were stimulated electrically for 2 min (20 Hz, 20 V, 2 ms). As a control, noradrenaline (1 microM) was infused into the portal vein for 2 minutes. RESULTS: During acute application of ethanol in portal concentrations of 50, 150 and 300 mM, which elevated basal glucose release, stimulation of hepatic nerves as well as portal noradrenaline infusion caused the same increase in glucose output and decrease in portal and arterial flow as in controls. Following chronic application of ethanol by feeding rats the Lieber-DeCarli liquid diet containing 5% (v/v) ethanol for 4 and 6 weeks, only nerve stimulation caused a significantly reduced enhancement of glucose output (50%, p < 0.025), whereas portal noradrenaline was as effective as in controls. Noradrenaline overflow was significantly reduced following nerve stimulation. CONCLUSION: The decrease in nerve stimulation-dependent glucose output and noradrenaline overflow in chronically ethanol fed rats indicates an impaired function of hepatic nerves.

Alcoholism↗

PubMed1997

Modulation by oxygen of zonal gene expression in liver studied in primary rat hepatocyte cultures.

The different endowment with key enzymes and thus different metabolic capacities of periportal and perivenous cell types led to the model of "metabolic zonation." The periportal and perivenous hepatocytes receive different signals owing to the decrease of substrate concentrations including O2 and hormone levels during passage of blood through the liver sinusoids. These different signal patterns should be important for the short-term regulation of metabolism and also for the long-term induction and maintenance of the different enzyme pathways by control of gene expression. The periportal to perivenous drop in oxygen tension was considered to be a key regulator in the zonated expression of carbohydrate-metabolizing enzymes. In primary hepatocyte cultures, glucagon activated the phosphoenolpyruvate carboxykinase (PCK) gene to higher levels under arterial than under venous oxygen. The insulin-dependent activation of the glucokinase (GK) gene was reciprocally modulated by oxygen. Exogenously added hydrogen peroxide mimicked the effects of arterial oxygen on both the glucagon-dependent PCK gene and the insulin-dependent GK activation. Therefore, the oxygen sensor could be a hydrogen peroxide-producing oxidase which could contain a heme group for "measuring" the O2 tension. This notion was corroborated by the finding that CO mimicked the positive effect of O2 on PCK gene activation. Transfection of PCK promoter-CAT gene constructs into primary hepatocytes showed that the oxygen modulation of the PCK gene activation occurred in the region -281/+69. The modulation by O2 was not mediated by isolated cAMP-responsive elements. Nuclear protein extracts prepared from hepatocytes cultured under venous PO2 as compared to arterial PO2 showed an enhanced binding activity to the promoter fragment -149/-43. Oxidative conditions such as H2O2 reduced the DNA-binding activity, thus supporting the role of H2O2 as a mediator in the O2 response of the PCK and GK genes.

Animals↗

PubMed1997

Role of oxygen in the zonation of carbohydrate metabolism and gene expression in liver.

Hepatocytes around the afferent (periportal) vessels differ from those around the efferent (perivenous) vessels in their contents of key enzymes, and therefore have different metabolic capacities. Thus, the model of "metabolic zonation" proposes that the periportal cells produce glucose via glycogenolysis and gluconeogenesis and that the perivenous cells utilize glucose via glycogen synthesis and glycolysis. The periportal and perivenous cells receive different signal patterns, because substrates including oxygen and hormones are degraded and products and mediators are formed during passage of blood through the liver. The different signal patterns should be important for both short-term regulation of metabolic rates and for long-term induction and maintenance of the enzyme equipments by control of gene expression. From the periportal to the perivenous zone, the concentration of the signal oxygen falls corresponding to a drop from about 13 (arterial) to 9 (mixed periportal) and then to 4 (hepatovenous) volume% gas atmosphere. For short-term regulation of metabolism, in perivenous-like cells net glucose production measured over a period of two hours was observed below 2%, net glycogen synthesis above 4%, and net lactate utilization above 6% oxygen. In periportal-like cells net glucose formation and net lactate utilization increased sharply from anoxia to 6% oxygen and then only moderately. For long-term regulation of gene expression, the glucagon (cAMP)-dependent activation of the PCK gene was modulated by oxygen. The transcriptional rate, the abundance of mRNA and the enzyme activity were increased to higher levels under arterial rather than under venous oxygen. Conversely, the insulin-dependent activation of the glucokinase gene was negatively modulated by oxygen. A heme protein appeared to be involved in oxygen sensing, since CO mimicked the effects of oxygen on the PCK gene. Hydrogen peroxide was produced by hepatocytes as a function of oxygen tension; exogenously added, it mimicked the effects of oxygen on PCK gene induction. Therefore, the heme protein containing an oxygen sensor could be a peroxide producing oxidase. It is not known at present whether the same oxygen sensor is also involved in the short-term regulation by oxygen of hepatic carbohydrate metabolism. Transfection of PCK promoter-CAT gene constructs into primary hepatocytes showed that oxygen modulated PCK gene activation in the region of -277/+73. This modulation was not mediated by isolated cAMP responsive elements.

Animals↗

PubMed1997

Diminution of the O2 responsiveness of the glucagon-dependent activation of the phosphoenolpyruvate carboxykinase gene in rat hepatocytes by long-term culture at venous PO2.

The glucagon-dependent activation of the phosphoenolpyruvate carboxykinase (PCK) gene within two hours is modulated by O2 in rat hepatocytes. It was the aim of the present study to test if this short-term modulation by O2 of the glucagon induction might be influenced by long-term culture of hepatocytes for 24 hours under different O2 tensions prior to glucagon induction. Cells were precultured for 24 hours at arterial O2 (16% O2) or venous O2 (8% O2), then induced within two to four hours with 1 nM glucagon each at arterial or venous O2. In arterial O2 precultured cells PCK mRNA and activity were induced to 100% at arterial O2 and to about 60% at venous O2. In venous O2 precultured cells PCK mRNA and activity were induced only to about 70% at arterial O2 and to about 60% at venous O2. Transfected PCK promoter (-2500)-CAT constructs were activated by glucagon with the same long-term modulatory effects of oxygen as the endogenous PCK gene. Gel mobility shift assays with nuclear extracts prepared from hepatocytes and a PCK promoter fragment ranging from -149 to -42 bp revealed one complex with a higher DNA binding activity when extracts of cells precultured for 24 hours under venous O2 as compared to arterial O2 were used. Therefore, the short-term modulation by O2 of PCK gene activation by glucagon was widely lost during preculture at low O2. This diminution of O2 sensitivity of PCK induction may be due to a nuclear protein or proteins which are induced by perivenous O2 tensions and bind to the PCK promoter.

Animals↗

PubMed1997

Mechanism of the impairment of the glucagon-stimulated phosphoenolpyruvate carboxykinase gene expression by interleukin-6 in rat hepatocytes: inhibition of the increase in cyclic 3',5' adenosine monophosphate and the downstream cyclic 3',5' adenosine monophosphate action.

In cultured rat hepatocytes, the gluconeogenic key enzyme, phosphoenolpyruvate carboxykinase (PCK), is induced by glucagon via elevation of cyclic 3',5' adenosine monophosphate (cAMP). The proinflammatory cytokine, interleukin-6 (IL-6), which in the liver together with IL-1beta and tumor necrosis factor alpha triggers the acute-phase response, had been shown to attenuate the glucagon-induced increase in PCK gene transcription, messenger (mRNA) levels, and enzyme activity. The molecular mechanism of this inhibition was investigated in the present study. Glucagon increased cyclic cAMP and PCK mRNA levels to a transient maximum twofold and fivefold, respectively. The increases were attenuated by IL-6. Forskolin, which stimulates adenylate cyclase activity, increased cAMP and PCK mRNA levels 1.6-fold and fivefold, respectively. However, IL-6 attenuated the forskolin-stimulated increase in PCK mRNA but not the increase in cAMP. This showed that IL-6 inhibited PCK mRNA increase in part by the attenuation of cAMP increase, but also beyond cAMP formation. This was confirmed in experiments in which PCK mRNA levels were increased by the nonhydrolyzable cAMP-analogue, chlorophenylthio (CPT)-cAMP. The increase in PCK mRNA was again attenuated by IL-6. In pertussis toxin- and in isobutylmethylxanthine-treated hepatocytes, IL-6 still inhibited the glucagon-stimulated increase in cAMP, indicating that IL-6 did not activate an inhibitory G-protein or phosphodiesterase, which could cause the impairment of cAMP increase. To demonstrate whether the inhibition of PCK gene expression by IL-6 beyond cAMP might be caused by the inhibition of the activation of the PCK gene promoter by cAMP, cultured rat hepatocytes were transfected with a luciferase reporter gene construct under the control of a PCK gene promoter fragment (base -979 to base +32). Luciferase activity was determined after stimulation of the cells with CPT-cAMP in the absence or presence of IL-6. CPT-cAMP increased luciferase activity by 1.7-fold, which was inhibited in the presence of IL-6. It is concluded that IL-6 had a dual inhibitory effect on the stimulation of PCK gene expression by glucagon. It inhibited the increase in cAMP at a site before cAMP formation by adenylate cyclase and at a site after cAMP formation, the activation of the PCK gene promoter by cAMP.

1-Methyl-3-isobutylxanthine↗

PubMed1996

Exclusive expression of the Gs-linked prostaglandin E2 receptor subtype 4 mRNA in mononuclear Jurkat and KM-3 cells and coexpression of subtype 4 and 2 mRNA in U-937 cells.

Prostaglandin E2 (PGE2) is regarded as a potent regulator of the immune system. It can regulate apoptosis in mononuclear cells and modulate the cytokine secretion pattern from T-helper cell subpopulations via an increase in cyclic AMP (cAMP). Of the 4 PGE2 receptor subtypes (EP1-EP4) that are defined pharmacologically by their affinity to subtype-specific ligands and their coupling to G proteins, EP2 and EP4 receptors couple to Gs. It is as yet unknown which of these two receptor subtypes mediates the immunomodulatory effects. By quantitative RT-PCR, the mRNA for EP4 receptors was demonstrated and quantified in the human mononuclear cell lines Jurkat, KM-3 and U-937. However, EP2 receptor mRNA was only present in U-937 cells and was 100-fold less abundant than EP4 receptor mRNA. PGE2 increased cAMP formation with an ED50 of 50-100 nM in all cell lines. cAMP formation was inhibited by the EP4R-specific antagonist AH23848. Since AH23848 inhibited PGE2-induced cAMP formation in U-937 cells to a similar extent as in Jurkat and KM-3, EP2 receptors seem to play, if any, only a secondary role for the PGE2-mediated cAMP formation in U-937 cells.

Biphenyl Compounds↗

PubMed1996

Defective propagation of signals generated by sympathetic nerve stimulation in the liver of connexin32-deficient mice.

The gap junctional protein connexin32 is expressed in hepatocytes, exocrine pancreatic cells, Schwann cells, and other cell types. We have inactivated the connexin32 gene by homologous recombination in the mouse genome and have generated homozygous connexin32-deficient mice that were viable and fertile but weighed on the average approximately 17% less than wild-type controls. Electrical stimulation of sympathetic nerves in connexin32-deficient liver triggered a 78% lower amount of glucose mobilization from glycogen stores, when compared with wild-type liver. Thus, connexin32-containing gap junctions are essential in mouse liver for maximal intercellular propagation of the noradrenaline signal from the periportal (upstream) area, where it is received from sympathetic nerve endings, to perivenous (downstream) hepatocytes. In connexin32-defective liver, the amount of connexin26 protein expressed was found to be lower than in wild-type liver, and the total area of gap junction plaques was approximately 1000-fold smaller than in wild-type liver. In contrast to patients with connexin32 defects suffering from X chromosome-linked Charcot-Marie-Tooth disease (CMTX) due to demyelination in Schwann cells of peripheral nerves, connexin32-deficient mice did not show neurological abnormalities when analyzed at 3 months of age. It is possible, however, that they may develop neurodegenerative symptoms at older age.

Animals↗

PubMed1996

Regulation of the gluconeogenic phosphoenolpyruvate carboxykinase and glycolytic aldolase A gene expression by O2 in rat hepatocyte cultures. Involvement of hydrogen peroxide as mediator in the response to O2.

Heme proteins acting as oxidases which produce H2O2 have been proposed to function as O2 sensors. In order to find out whether the modulation by O2 of PCK gene activation and the stimulation of the ALD A gene by venous O2 operate via H2O2, the effects of different concentrations of H2O2 and catalase as H2O2 scavenger were studied in rat hepatocyte cultures under different O2 tensions. Primary hepatocytes were treated with 0.1 nM glucagon, 50 microM H2O2 and/or 100 micrograms/ml catalase each at arterial O2 or venous pO2. PCK mRNA was induced by glucagon maximally under arterial O2 and only half maximally under venous O2. ALD A mRNA was induced only by venous O2. H2O2 enhanced the induction of PCK mRNA to similar levels under venous O2 tensions and the induction of ALD A mRNA under both O2 was completely inhibited. Addition of catalase antagonized the actions of H2O2 completely. These findings support the hypothesis that an H2O2-generating heme protein is involved in the O2 sensing system regulating gluconeogenic and glycolytic gene expression in response to O2.

Animals↗

PubMed1996

Molecular cloning, sequencing and expression of the cDNA of the mitochondrial form of phosphoenolpyruvate carboxykinase from human liver.

In human liver, phosphoenolpyruvate carboxykinase (PCK; EC 4.1.1.32) is about equally distributed between cytosol and mitochondria in contrast with rat liver in which it is essentially a cytosolic enzyme. Recently, the isolation of the gene and cDNA of the human cytosolic enzyme has been reported [Ting, Burgess, Chamberlian, Keith, Falls and Meisler (1993) Genomics 16, 698-706; Stoffel, Xiang, Espinosa, Cox, Le Beau and Bell (1993) Hum. Mol. Genet. 2, 1-4]. It was the goal of this investigation to isolate the cDNA of the human mitochondrial form of hepatic PCK. A human liver cDNA library was screened with a rat cytosolic PCK cDNA probe comprising sequences from exons 2 to 9. A cDNA clone was isolated which had overall a 68% DNA sequence and a 70% deduced amino acid sequence identity with the human cytosolic PCK cDNA. Without the flanking 270 bases (=90 amino acids) each at the 5' and 3' end, the sequence identity was 73% on the DNA and 78% on the amino acid level. The isolated cDNA had an open reading frame of 1920 bp; it was 54 bp (equivalent to 18 amino acids) longer than that of human or rat cytosolic PCK cDNA. The isolated cDNA was cloned into the eukaryotic expression vector pcDNAI and transfected into human embryonal kidney cells HEK293; PCK activity was increased by 3-fold in the mitochondria, which normally contain 70% of total PCK activity, but not in the cytosol. The isolated cDNA was also transfected into cultured rat hepatocytes; again, PCK activity was enhanced by about 40-fold in the mitochondria, which normally possess only 10% of total PCK activity, but not in the cytosol. In the rat hepatocytes only the endogenous cytosolic PCK and not the transfected mitochondrial PCK was induced 3-fold with glucagon. Comparison of the amino acid sequences deduced from the isolated cDNA with human and rat cytosolic PCK showed that the additional 18 amino acids were located at the N-terminus of the protein and probably constitute a mitochondrial targeting signal. Northern-blot analyses revealed the human mitochondrial PCK mRNA to be 2.25 kb long, about 0.6 kb shorter than the mRNA of the cytosolic PCK. Primer extension experiments showed that the 5'-untranslated region of mitochondrial PCK mRNA was 134 nucleotides in length.

Amino Acid Sequence↗

PubMed1996

Inhibition of anaphylatoxin C3a- and C5a- but not nerve stimulation- or Noradrenaline-dependent increase in glucose output and reduction of flow in Kupffer cell-depleted perfused rat livers.

In isolated in situ perfused rat livers, infusion of anaphylatoxins C3a and C5a, activation peptides of the complement system, as well as stimulation of sympathetic hepatic nerves have been shown to increase hepatic glucose output and to reduce hepatic flow. These effects were mediated via an at least partially prostanoid-dependent intercellular signalling chain between nonparenchymal cells and hepatocytes. Kupffer cells have been implicated as the source of prostanoids in the anaphylatoxin-dependent signalling chain and Ito cells in the nerve stimulation-dependent signalling chain, because anaphylatoxins and noradrenaline increased prostanoid synthesis in isolated Kupffer and Ito cells, respectively. To further corroborate this hypothesis, anaphylatoxins were infused and hepatic nerves were stimulated in perfused rat livers in which Kupffer cells had been largely depleted by treatment of the animals with gadolinium chloride. Native human anaphylatoxin C3a (nhC3a) and recombinant rat anaphylatoxin C5a (rrC5a) increased prostanoid formation as well as glucose output and reduced flow in perfused rat liver. In Kupffer cell-depleted rat livers, the nhC3a- and rrC5a-mediated prostanoid formation was nearly abolished, and the increase in glucose output and the reduction of flow were reduced to between 30% and 50% (area under the curve [AUC]) of control livers. In contrast, stimulation of hepatic nerves increased glucose output and reduced flow to a similar extent in Kupffer cell-depleted livers as in control livers. These results indicate that Kupffer cells were not involved in the prostanoid-mediated nerve stimulation-dependent increase in glucose output and reduction of flow. Kupffer cells seemed, however, to be at least one major source of the anaphylatoxin-mediated prostanoid formation and, consequently, stimulation of glucose release and flow reduction in perfused liver. Because the metabolic and hemodynamic anaphylatoxin effects were not completely blocked in livers of gadolinium-treated animals, either Kupffer cells may not have been entirely eliminated, or yet another nonparenchymal cell type and mediator might be involved in the anaphylatoxin-elicited intercellular communication between nonparenchymal cells and hepatocytes.

Anaphylatoxins↗

PubMed1996

Acute increase by portal insulin in intestinal glucose absorption via hepatoenteral nerves in the rat.

BACKGROUND & AIMS: Insulin exerts a strict short-term control of glucose disappearance by glucose storage as well as degradation in the liver and peripheral insulin target tissues, but an acute control of glucose appearance by glucose absorption in the intestine is as yet unknown. The aim of the present study was to evaluate, whether insulin acutely modulates intestinal glucose absorption. METHODS: In the isolated, nonrecirculating joint perfusion of the small bowel and liver of the rat via the celiac trunc and the superior mesenteric artery, glucose absorption was examined without and with infusion of insulin via the portal vein. RESULTS: Portal insulin enhanced acutely intestinal glucose absorption. This thus far unknown stimulatory effect of portal insulin was dose-dependent and detectable at physiological insulin concentrations. Atropine infused into the superior mesenteric artery completely prevented the insulin-dependent increase in intestinal glucose absorption, and carbachol caused a similar increase as portal insulin. CONCLUSIONS: Portal insulin dose-dependently generated a signal in the liver or portal vein. This signal was transmitted in a retrograde direction against the blood stream in the portal vein to the small intestine via hepatoenteral muscarinic nerves. This signal markedly increased intestinal glucose absorption.

Animals↗

PubMed1996

Zonation of parenchymal and nonparenchymal metabolism in liver.

The enormous number of different liver functions are carried out by parenchymal and four main types of nonparenchymal cells, either alone or in cooperation. Although the liver tissue is uniform on the level of histology, it is heterogenous on the level of morphometry and histochemistry. This heterogeneity is related to the blood supply; cells located in the upstream or periportal zone differ from those in the downstream or perivenous zone in their equipment with key enzymes, translocators, receptors, and subcellular structures and therefore have different functional capacities. This is the basis of the model of metabolic zonation, according to which glucose release from glycogen and via gluconeogenesis, amino acid utilization and ammonia detoxification, protective metabolism, bile formation, and the synthesis of certain plasma proteins such as albumin and fibrinogen occur mainly in the periportal area, whereas glucose utilization, xenobiotic metabolism, and the formation of other plasma proteins such as alpha 1-antitrypsin or alpha-fetoprotein occur predominantly in the perivenous zone. The mor- phologic and functional heterogeneity is the result of zonal differences in the activation of the cellular genome caused by gradients in oxygen, substrate, hormone, and mediator levels, in innervation, as well as in cell-to-cell and cell-to-biomatrix interactions.

Endothelium↗