Dataset Information

Dynamic Metabolic Zonation of the Hepatic Glucose Metabolism Is Accomplished by Sinusoidal Plasma Gradients of Nutrients and Hormones.

ABSTRACT: Being the central metabolic organ of vertebrates, the liver possesses the largest repertoire of metabolic enzymes among all tissues and organs. Almost all metabolic pathways are resident in the parenchymal cell, hepatocyte, but the pathway capacities may largely differ depending on the localization of hepatocytes within the liver acinus-a phenomenon that is commonly referred to as metabolic zonation. Metabolic zonation is rather dynamic since gene expression patterns of metabolic enzymes may change in response to nutrition, drugs, hormones and pathological states of the liver (e.g., fibrosis and inflammation). This fact has to be ultimately taken into account in mathematical models aiming at the prediction of metabolic liver functions in different physiological and pathological settings. Here we present a spatially resolved kinetic tissue model of hepatic glucose metabolism which includes zone-specific temporal changes of enzyme abundances which are driven by concentration gradients of nutrients, hormones and oxygen along the hepatic sinusoids. As key modulators of enzyme expression we included oxygen, glucose and the hormones insulin and glucagon which also control enzyme activities by cAMP-dependent reversible phosphorylation. Starting with an initially non-zonated model using plasma profiles under fed, fasted and diabetic conditions, zonal patterns of glycolytic and gluconeogenetic enzymes as well as glucose uptake and release rates are created as an emergent property. We show that mechanisms controlling the adaptation of enzyme abundances to varying external conditions necessarily lead to the zonation of hepatic carbohydrate metabolism. To the best of our knowledge, this is the first kinetic tissue model which takes into account in a semi-mechanistic way all relevant levels of enzyme regulation.

SUBMITTER: Berndt N

PROVIDER: S-EPMC6315134 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Dynamic Metabolic Zonation of the Hepatic Glucose Metabolism Is Accomplished by Sinusoidal Plasma Gradients of Nutrients and Hormones.

Berndt Nikolaus N Holzhütter Hermann-Georg HG

Frontiers in physiology 20181212

Being the central metabolic organ of vertebrates, the liver possesses the largest repertoire of metabolic enzymes among all tissues and organs. Almost all metabolic pathways are resident in the parenchymal cell, hepatocyte, but the pathway capacities may largely differ depending on the localization of hepatocytes within the liver acinus-a phenomenon that is commonly referred to as metabolic zonation. Metabolic zonation is rather dynamic since gene expression patterns of metabolic enzymes may cha ...[more]

PMID: 30631280

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Project description:Background & aimsLiver sinusoidal endothelial cells (SECs) promote the proliferation of hepatocytes during liver regeneration. However, the specific subset of SECs and its mechanisms during the process remain unclear. In this study, we investigated the potential role of c-kit+ SECs, a newly identified subset of SECs in liver regeneration.MethodsPartial hepatectomy mice models were established to induce liver regeneration. Hepatic c-kit expression was detected by quantitative reverse-transcription polymerase chain reaction, immunofluorescent staining, and fluorescence-activated cell sorting. VE-cadherin-cyclization recombinase-estrogen receptor (Cdh5-Cre-ERT) Notch intracellular domain and Cdh5-Cre recombination signal binding protein Jκfloxp mice were introduced to mutate Notch signaling. c-Kit+ SECs were isolated by magnetic beads. Single-cell RNA sequencing was performed on isolated SECs. Liver injuries were induced by CCl4 or quantitative polymerase chain reaction injection.ResultsHepatic c-kit is expressed predominantly in SECs. Liver resident SECs contribute to the increase of c-kit during partial hepatectomy-induced liver regeneration. Isolated c-kit+ SECs promote hepatocyte proliferation in vivo and in vitro by facilitating angiocrine. The distribution of c-kit shows distinct spatial differences that are highly coincident with the liver zonation marker wingless-type MMTV integration site family, member2 (Wnt2). Notch mutation reshapes the c-kit distribution and liver zonation, resulting in altered hepatocyte proliferation. c-Kit+ SECs were shown to regulate hepatocyte regeneration through angiocrine in a Wnt2-dependent manner. Activation of the Notch signaling pathway weakens liver regeneration by inhibiting positive regulatory effects of c-kit+ SECs on hepatocytes. Furthermore, c-kit+ SEC infusion attenuates toxin-induced liver injuries in mice.ConclusionsOur results suggest that c-kit+ SECs contributes to liver zonation and regeneration through Wnt2 and is regulated by Notch signaling, providing opportunities for novel therapeutic approaches to liver injury in the future. Transcript profiling: GEO (accession number: GSE134037).

Project description:The activities of several hepatic enzymes are preferentially zonated to the periportal or perivenous cells of the liver acinus. Employing dual-digitonin-pulse perfusion of rat liver in the study of acetyl-CoA carboxylase (ACC), we have identified a heretofore unrecognized feature of hepatic zonation, namely an intrahepatic gradient in enzyme specific activity. ACC activity shows a relative periportal localization in normally feeding rats, even when corrected for ACC protein mass. In contrast with results previously reported by us [Evans, Quistorff & Witters (1989) Biochem. J. 259, 821-829], the total mass of both hepatic ACC isoenzymes was not found to differ between the two hepatic zones in the present study. In perfusion eluates from fed animals, periportal ACC displays enhanced citrate reactivity and two kinetic components of acetyl-CoA reactivity; the largest periportal/perivenous gradient (5-fold) is accounted for by a species with a lower Km for acetyl-CoA. The zonal gradient in ACC maximal velocity, measured in eluates from fed rats, does not persist after ACC purification, although the isolated periportal enzyme, like dephosphorylated ACC, has a lower activation constant for citrate. Total ACC protein phosphatase activity is higher in periportal eluates, but no differences in the activities of either a 5'-AMP-activated ACC kinase or the cyclic-AMP-dependent protein kinase are noted between the hepatic zones. The induction of total hepatic ACC mass and specific activity, on fasting/refeeding with a high-carbohydrate diet, abolishes the periportal/perivenous activity gradient, largely owing to a selective activation of perivenous enzyme. Nutritional induction is also accompanied by a marked alteration in ACC acetyl-CoA kinetics and abolition of the gradient in total ACC phosphatase. These studies indicate that hepatic enzyme zonation, which is often attributed to differential expression of enzyme protein, may result from zonal variations in enzyme specific activity, owing to differences in allosteric regulation and/or covalent modification.

Dataset Information

Dynamic Metabolic Zonation of the Hepatic Glucose Metabolism Is Accomplished by Sinusoidal Plasma Gradients of Nutrients and Hormones.

Publications

Dynamic Metabolic Zonation of the Hepatic Glucose Metabolism Is Accomplished by Sinusoidal Plasma Gradients of Nutrients and Hormones.

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