scholarly journals Muscle-Liver Substrate Fluxes in Exercising Humans and Potential Effects on Hepatic Metabolism

2019 ◽  
Vol 105 (4) ◽  
pp. 1196-1209 ◽  
Author(s):  
Chunxiu Hu ◽  
Miriam Hoene ◽  
Peter Plomgaard ◽  
Jakob S Hansen ◽  
Xinjie Zhao ◽  
...  
Keyword(s):  
Energy Homeostasis ◽  
Transcriptional Response ◽  
Hepatic Metabolism ◽  
Hepatic Function ◽  
Hepatic Uptake ◽  
Degree Of Saturation ◽  
Liquid Chromatography Mass Spectrometry ◽  
Acute Bout ◽  
Liver Transcriptome ◽  
High Degree

Abstract Context The liver is crucial to maintain energy homeostasis during exercise. Skeletal muscle-derived metabolites can contribute to the regulation of hepatic metabolism. Objective We aim to elucidate which metabolites are released from the working muscles and taken up by the liver in exercising humans and their potential influence on hepatic function. Methods In two separate studies, young healthy men fasted overnight and then performed an acute bout of exercise. Arterial-to-venous differences of metabolites over the hepato-splanchnic bed and over the exercising and resting leg were investigated by capillary electrophoresis- and liquid chromatography-mass spectrometry metabolomics platforms. Liver transcriptome data of exercising mice were analyzed by pathway analysis to find a potential overlap between exercise-regulated metabolites and activators of hepatic transcription. Results During exercise, hepatic O2 uptake and CO2 delivery were increased two-fold. In contrast to all other free fatty acids (FFA), those FFA with 18 or more carbon atoms and a high degree of saturation showed a constant release in the liver vein and only minor changes by exercise. FFA 6:0 and 8:0 were released from the working leg and taken up by the hepato-splanchnic bed. Succinate and malate showed a pronounced hepatic uptake during exercise and were also released from the exercising leg. The transcriptional response in the liver of exercising mice indicates the activation of HIF-, NRF2-, and cAMP-dependent gene transcription. These pathways can also be activated by succinate. Conclusion Metabolites circulate between working muscles and the liver and may support the metabolic adaption to exercise by acting both as substrates and as signaling molecules.

Hepatic metabolism during fasting-refeeding transition in conscious pregnant rabbits

1992 ◽  
Vol 262 (6) ◽  
pp. E899-E905 ◽  
Author(s):  
M. C. Pere ◽  
A. Baudelin ◽  
K. Briggs ◽  
M. Gilbert
Keyword(s):  
Insulin Resistance ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Hepatic Metabolism ◽  
Hepatic Uptake ◽  
Mixed Meal ◽  
Fick Principle ◽  
Pregnant Females ◽  
Glucose Output ◽  
Beta Hydroxybutyrate

The aim of the present study was to determine changes induced by pregnancy in the hepatic handling of nutrients during the fasting-refeeding transition. Net hepatic and gut substrate fluxes were determined by the Fick principle in conscious pregnant (day 30) and nonpregnant rabbits in the 2 h after consumption of a mixed meal. Hepatic glucose production was suppressed by approximately 50% in both groups from 15 to 90 min. Pregnant rabbits returned to control levels at 120 min. Pregnant females displayed a larger gut glucose output and a greater arterial hyperglycemia. The hepatic and gut balance of lactate as well as the arterial level was almost unchanged. In pregnant females the hepatic uptake and arterial concentration of free fatty acids (FFA) remained almost unchanged, whereas these measures decreased in nonpregnant females by approximately 55 and approximately 80%, respectively, at 120 min. The decline in hepatic output of beta-hydroxybutyrate was similar in both groups. In pregnant rabbits arterial levels of beta-hydroxybutyrate did not parallel changes in the hepatic release as in nonpregnant females. Pregnant females displayed a greater hyperinsulinemia both in the portal vein and the artery over the first hour. It is concluded that, in pregnant rabbits fed a mixed meal, the ability of the liver to handle glucose is impaired because of insulin resistance. The latter brings about a greater and prolonged arterial hyperglycemia, which is reinforced by peripheral insulin resistance. Furthermore, the higher level of FFA may also contribute to the hyperglycemia. As a result, a greater amount of glucose is diverted to other sites, presumably the uterus.

Hepatic function in rats after spaceflight: effects on lipids, glycogen, and enzymes

1987 ◽  
Vol 252 (2) ◽  
pp. R222-R226 ◽  
Author(s):  
A. H. Merrill ◽  
E. Wang ◽  
D. P. Jones ◽  
J. L. Hargrove
Keyword(s):  
Specific Activity ◽  
Cytochrome B5 ◽  
Hepatic Metabolism ◽  
Microsomal Protein ◽  
Hepatic Function ◽  
Tyrosine Aminotransferase ◽  
Fatty Acyl ◽  
Blood Cholesterol ◽  
Serine Palmitoyltransferase ◽  
Coa Reductase

The inclusion of rats aboard Spacelab 3 (SL-3) allowed analyses of liver lipids, glycogen, hepatic enzymes of cholesterol, glycerolipid and sphingolipid biosynthesis, and other enzyme activities. Glycogen content was markedly elevated in livers from the flight animals compared with controls. Cholesterol was 24% (P less than 0.04) lower in livers from the experimental groups, whereas blood cholesterol was 19% higher (P less than 0.05). The activity of 3-hydroxy-3-methylglutaryl-CoA reductase, the rate-limiting enzyme of steroid biosynthesis, was 80% lower (P less than 0.01). Total phospholipids and sphingolipid levels did not differ significantly. The specific activity of fatty acyl-CoA synthetase, which is responsible for activation of fatty acids, was 37% (P less than 0.05) higher in microsomes from the rats on SL-3; however, since these animals had 25% less microsomal protein (P less than 0.02), there was no difference per gram of liver. The initial enzymes of sphingolipid and glycerolipid biosynthesis were assayed; serine palmitoyltransferase was 40% lower (P less than 0.01), and glycerol 3-phosphate acyltransferase did not differ. Hepatic cytochrome P-450 content decreased by 50% after spaceflight. Enzymes that did not differ significantly between the two groups include cytochrome b5, glutathione S-transferase, tyrosine aminotransferase, aspartate aminotransferase, and cystathionase. These findings suggest that spaceflight alters hepatic metabolism of several classes of compounds.

Etoposide kinetics in patients with obstructive jaundice.

1990 ◽  
Vol 8 (6) ◽  
pp. 1101-1107 ◽  
Author(s):  
K R Hande ◽  
S N Wolff ◽  
F A Greco ◽  
J D Hainsworth ◽  
G Reed ◽  
...  
Keyword(s):  
Obstructive Jaundice ◽  
Urinary Excretion ◽  
Hepatic Metabolism ◽  
Study Groups ◽  
Hepatic Function ◽  
Volume Of Distribution ◽  
Metabolic Clearance ◽  
Total Clearance ◽  
Dose Reductions ◽  
Made In

The kinetics and urinary excretion of etoposide and etoposide glucuronide were determined in 11 patients with obstructive jaundice (bilirubin greater than 2.0 mg/dL) and in 23 patients with normal renal and hepatic function. Mean (+/- SE) measurements of clearance (24.5 +/- 2.06 v 26.5 +/- 2.05 mL/min/m2), half-life (5.7 +/- 0.5 v 6.4 +/- 0.5 hours), and volume of distribution (12.4 +/- 1.1 v 13.7 +/- 1.6 L/m2) were not significantly different in patients with jaundice when compared with controls. Similarly, etoposide kinetics in three patients determined during a period of hyperbilirubinemia were not different from measurements made in the same patients following resolution of their obstructive jaundice. In patients with jaundice, 46% of an administered etoposide dose was excreted in the urine as etoposide compared with 35% in controls (P = .15). Urinary excretion of etoposide glucuronide accounted for 29% of an administered etoposide dose in control patients and 15% in those with hepatic obstruction (P = .03). Biliary etoposide excretion measured in four patients with T-tubes was insignificant (less than 2.0% of an administered dose). The calculated renal clearance of etoposide was 11.5 mL/min/m2 in patients with jaundice and 10.4 mL/min/m2 in controls (P = .53). Respective metabolic clearance was 4.9 and 6.9 mL/min/m2 in these two study groups (P = .13). Although hepatic metabolism of etoposide may be slightly decreased in patients with obstructive jaundice, a modest increase in renal etoposide excretion appears to compensate for this change, so that total clearance is similar in the patients with jaundice when compared with controls. No etoposide dose reductions appear to be needed in treating patients with obstructive jaundice who have normal renal function.

scholarly journals Bile Acid Uptake Transporters as Targets for Therapy

2017 ◽  
Vol 35 (3) ◽  
pp. 251-258 ◽  
Author(s):  
Davor Slijepcevic ◽  
Stan F.J. van de Graaf
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Energy Homeostasis ◽  
Sodium Taurocholate ◽  
Hepatic Uptake ◽  
Farnesoid X Receptor ◽  
Acid Uptake ◽  
Bile Acid Uptake ◽  
Uptake Transporters ◽  
Conjugated Bile Acids

Background: Bile acids are potent signaling molecules that regulate glucose, lipid and energy homeostasis predominantly via the bile acid receptors farnesoid X receptor (FXR) and transmembrane G protein-coupled receptor 5 (TGR5). The sodium taurocholate cotransporting polypeptide (NTCP) and the apical sodium dependent bile acid transporter (ASBT) ensure an effective circulation of (conjugated) bile acids. The modulation of these transport proteins affects bile acid localization, dynamics and signaling. The NTCP-specific pharmacological inhibitor myrcludex B inhibits hepatic uptake of conjugated bile acids. Multiple ASBT-inhibitors are already in clinical trials to inhibit intestinal bile acid uptake. Here, we discuss current insights into the consequences of targeting bile acid uptake transporters on systemic and intestinal bile acid dynamics and discuss the possible therapeutic applications that evolve as a result.

scholarly journals THE EQUILIBRIUM BETWEEN CYTOCHROME OXIDASE AND CARBON MONOXIDE

1957 ◽  
Vol 40 (4) ◽  
pp. 593-608 ◽  
Author(s):  
George Wald ◽  
David W. Allen
Keyword(s):  
Carbon Monoxide ◽  
Cytochrome Oxidase ◽  
Hill Equation ◽  
Bohr Effect ◽  
Degree Of Saturation ◽  
Percentage Saturation ◽  
Equilibrium Function ◽  
Hyperbolic Equilibrium ◽  
High Degree ◽  
The Hill

An evolution argument which attempted to trace the development of hemoglobins from such respiratory pigments as cytochrome oxidase presupposed that the latter possesses, in addition to its high affinity for oxygen, an approximately hyperbolic equilibrium function, and little if any Bohr effect (decline in affinity for oxygen with rise in acidity). Since cytochrome oxidase, unlike hemoglobin, is irreversibly oxidized by oxygen, the present experiments examine its combination with carbon monoxide, with which, like hemoglobin, it yields a true equilibrium. In all known hemoglobins the form of the equilibrium function and the vigor of the Bohr effect are similar with carbon monoxide and with oxygen, so that observations involving the former gas are relevant to the relations of the latter. The equilibrium function of cytochrome oxidase with carbon monoxide—percentage saturation vs. partial pressure of CO—is slightly inflected (in the Hill equation n = 1.26; for a hyperbola, n = 1). No Bohr effect is present in the range of pH 7–8. The pressure of carbon monoxide at which half-saturation occurs (p50) is about 0.17 mm. at 10–13°C. The affinity for carbon monoxide is therefore higher than commonly supposed. These properties are consistent with the evolution argument. They are important also for the physiological functioning of cytochrome oxidase, the nearly hyperbolic equilibrium function facilitating a high degree of saturation, and the lack of Bohr effect making this enzyme impervious to hyperacidity. The slight inflection of the equilibrium function shows that the Fe-porphyrin units of cytochrome oxidase interact to a degree, hence that the enzyme must contain more than one such unit per molecule. It is suggested that in cytochrome oxidase two Fe-porphyrin groups may unite with one oxygen in the manner Fe++-O2-Fe++; and that the evolution of hemoglobins proceeded over a first stage in which the hemes were separated so that each combines with only one molecule of oxygen, so tending to remain reduced; to a further stage in which the separated hemes interact through the protein to facilitate one another in combining with oxygen.

Hepatic function in rats with dietary-induced fatty liver, as measured by the uptake of indocyanine green

1982 ◽  
Vol 47 (3) ◽  
pp. 391-397 ◽  
Author(s):  
F. Jahoor ◽  
Alan A. Jackson
Keyword(s):  
Indocyanine Green ◽  
Fatty Liver ◽  
G Protein ◽  
Fatty Infiltration ◽  
Hepatic Function ◽  
Hepatic Uptake ◽  
Deficient Diet ◽  
Liver Lobule ◽  
Periportal Zone ◽  
Predominant Effect

1. The hepatic uptake of indocyanine green (ICG) has been measured in rats receiving a 50 g protein/kg diet for 6, 12 or 20 d or a choline-deficient diet for 2 or 6 d.2. There was no effect on ICG uptake on the choline-deficient diet, although all the rats developed an intense fatty infiltration of the liver by 6 d.3. The rats on the 50 g protein/kg diet showed impaired uptake of ICG at 6, 12 and 20 d, which appeared to be related to the extent of fatty infiltration.4. It is concluded that ICG uptake is predominantly a function of the periportal zone of the liver lobule, and therefore likely to be sensitive to insults that exert their predominant effect in this zone.

Uptake of unconjugated bilirubin by isolated rat hepatocytes

1979 ◽  
Vol 236 (1) ◽  
pp. C9-C14 ◽  
Author(s):  
T. Iga ◽  
D. L. Eaton ◽  
C. D. Klaassen
Keyword(s):  
Lipid Membrane ◽  
Rat Hepatocytes ◽  
Isolated Hepatocytes ◽  
Hepatic Uptake ◽  
Unconjugated Bilirubin ◽  
Metabolic Inhibitors ◽  
Isolated Rat Hepatocytes ◽  
Intracellular Binding ◽  
High Degree ◽  
Isolated Rat

The mechanism responsible for the hepatic uptake of unconjugated bilirubin was examined in isolated rat hepatocytes from control and phenobartital-pretreated rats. The uptake was extremely rapid and the equilibrium between cell and medium was attained within 60 s with a 100-fold higher concentration in the cell than the medium. The initial velocity of uptake (Vo) exhibited a linear relationship to the bilirubin concentration in the medium. Pretreatment of cells with various metabolic inhibitors had no effect on the uptake of unconjugated bilirubin. Ouabain did significantly decrease Vo, but replacement of sodium ion with choline or lithium had no effect on bilirubin uptake. The organic acids sulfobromophthalein (112 muM) and taurocholic acid (50 (muM) and two steroidal compounds, diethylstilbestrol (50 muM) and spironolactone (50 muM), had no effect on the uptake of bilirubin. It is suggested that bilirubin gains access to the hepatocyte interior by passive diffusion into and through the lipid membrane and that intracellular binding may explain the high degree of bilirubin accumulation associated with the isolated hepatocytes.

scholarly journals Glucose Controls Nuclear Accumulation, Promoter Binding, and Transcriptional Activity of the MondoA-Mlx Heterodimer

2010 ◽  
Vol 30 (12) ◽  
pp. 2887-2895 ◽  
Author(s):  
Christopher W. Peterson ◽  
Carrie A. Stoltzman ◽  
Michael P. Sighinolfi ◽  
Kyoung-Sim Han ◽  
Donald E. Ayer
Keyword(s):  
Energy Homeostasis ◽  
Leucine Zipper ◽  
Metabolic Diseases ◽  
Transcriptional Response ◽  
Activation Function ◽  
Cellular Level ◽  
Nuclear Accumulation ◽  
Glucose Levels ◽  
Helix Loop Helix ◽  
Intracellular Glucose

ABSTRACT Maintenance of energy homeostasis is a fundamental requirement for organismal fitness: defective glucose homeostasis underlies numerous metabolic diseases and cancer. At the cellular level, the ability to sense and adapt to changes in intracellular glucose levels is an essential component of this strategy. The basic helix-loop-helix-leucine zipper (bHLHZip) transcription factor complex MondoA-Mlx plays a central role in the transcriptional response to intracellular glucose concentration. MondoA-Mlx complexes accumulate in the nucleus in response to high intracellular glucose concentrations and are required for 75% of glucose-induced transcription. We show here that, rather than simply controlling nuclear accumulation, glucose is required at two additional steps to stimulate the transcription activation function of MondoA-Mlx complexes. Following nuclear accumulation, glucose is required for MondoA-Mlx occupancy at target promoters. Next, glucose stimulates the recruitment of a histone H3 acetyltransferase to promoter-bound MondoA-Mlx to trigger activation of gene expression. Our experiments establish the mechanistic circuitry by which cells sense and respond transcriptionally to various intracellular glucose levels.

scholarly journals Effects of guar gum and cellulose on glucose absorption, hormonal release and hepatic metabolism in the pig

1992 ◽  
Vol 68 (3) ◽  
pp. 693-700 ◽  
Author(s):  
C. Simões Nunes ◽  
K. Malmlöf
Keyword(s):  
Portal Vein ◽  
Guar Gum ◽  
Latin Square ◽  
Glucagon Secretion ◽  
Hepatic Metabolism ◽  
Gastric Inhibitory Polypeptide ◽  
Hepatic Uptake ◽  
Metabolic Effects ◽  
Adaptation Period ◽  
Large White

Six Large White pigs (mean body-weight 59 (se 1.7) kg) were surgically fitted with permanent catheters in the portal vein, the brachiocephalic artery and the right hepatic vein, as well as with electromagnetic flow probes around the portal vein and the hepatic artery, and allowed to recover. The non-anaesthetized animals were given a basal non-fibre diet (diet A) alone or together with 60 g guar gum/kg (diet B) or 150 g purified cellulose/kg (diet C) by substitution for mica. The diets were given for weekly periods and according to a replicated 3x3 Latin square design. On the last day of each such adaptation period, test meals of 800 g were given before blood sampling. Sampling was continued for 8 h. Guar gum strongly reduced glucose apparent absorption without changing the absorption and the hepatic uptake profiles. Production rates of insulin, gastric inhibitory polypeptide and insulin-like growth factor-1 (IGF-1) were lowest after guar gum ingestion. However, the reductions in peripheral blood insulin levels caused by guar gum were not associated with a change in hepatic insulin extraction. IGF-1 appeared to be strongly secreted by the gut, whereas the liver had a net uptake of the peptide. Ingestion of guar gum increased the hepatic extraction coefficient of gut-produced IGF-1. Guar gum ingestion appeared also to decrease glucagon secretion.Cellulose at the level consumed had very few effects on the variables considered.It is suggested that the modulation of intestinal mechanisms by guar gum was sufficient to mediate the metabolic effects described

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