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Zonation of nitrogen and glucose metabolism gene expression upon acute liver damage in mouse.

ABSTRACT: Zonation of metabolic activities within specific structures and cell types is a phenomenon of liver organization and ensures complementarity of variant liver functions like protein production, glucose homeostasis and detoxification. To analyze damage and regeneration of liver tissue in response to a toxic agent, expression of liver specific enzymes was analyzed by in situ hybridization in mouse over a 6 days time course following carbon tetrachloride (CCl4) injection. CCl4 mixed with mineral oil was administered to BALB/c mice by intraperitoneal injection, and mice were sacrificed at different time points post injection. Changes in the expression of albumin (Alb), arginase (Arg1), glutaminase 2 (Gls2), Glutamine synthetase (Gs), glucose-6-phosphatase (G6pc), glycogen synthase 2 (Gys2), Glycerinaldehyd-3-phosphat-Dehydrogenase (Gapdh), Cytochrom p450 2E1 (Cyp2e1) and glucagon receptor (Gcgr) genes in the liver were studied by in situ hybridization and qPCR. We observed significant changes in gene expression of enzymes involved in nitrogen and glucose metabolism and their local distribution following CCl4 injury. We also found that Cyp2e1, the primary metabolizing enzyme for CCl4, was strongly expressed in the pericentral zone during recovery. Furthermore, cells in the damaged area displayed distinct gene expression profiles during the analyzed time course and showed complete recovery with strong albumin production 6 days after CCl4 injection. Our results indicate that despite severe damage, liver cells in the damaged area do not simply die but instead display locally adjusted gene expression supporting damage response and recovery.

SUBMITTER: Ghafoory S

PROVIDER: S-EPMC3798318 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Zonation of nitrogen and glucose metabolism gene expression upon acute liver damage in mouse.

Ghafoory Shahrouz S Breitkopf-Heinlein Katja K Li Qi Q Scholl Catharina C Dooley Steven S Wölfl Stefan S

PloS one 20131017 10

Zonation of metabolic activities within specific structures and cell types is a phenomenon of liver organization and ensures complementarity of variant liver functions like protein production, glucose homeostasis and detoxification. To analyze damage and regeneration of liver tissue in response to a toxic agent, expression of liver specific enzymes was analyzed by in situ hybridization in mouse over a 6 days time course following carbon tetrachloride (CCl4) injection. CCl4 mixed with mineral oil ...[more]

PMID: 24147127

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Project description:BackgroundNOD-like receptors (NLR) are intracellular sensors of the innate immune system, with the NLRP3 being a pro-inflammatory member that modulates cardiac ischemia-reperfusion injury (IRI) and metabolism. No information is available on a possible role of anti-inflammatory NLRs on IRI and metabolism in the intact heart. Here we hypothesize that the constitutively expressed, anti-inflammatory mitochondrial NLRX1, affects IRI and metabolism of the isolated mouse heart.MethodsIsolated C57Bl/6J and NLRX1 knock-out (KO) mouse hearts were perfused with a physiological mixture of the essential substrates (lactate, glucose, pyruvate, fatty acid, glutamine) and insulin. For the IRI studies, hearts were subjected to either mild (20 min) or severe (35 min) ischemia and IRI was determined at 60 min reperfusion. Inflammatory mediators (IL-6, TNFα) and survival pathways (mito-HKII, p-Akt, p-AMPK, p-STAT3) were analyzed at 5 min of reperfusion. For the metabolism studies, hearts were perfused for 35 min with either 5.5 mM 13C-glucose or 0.4 mM 13C-palmitate under normoxic conditions, followed by LC-MS analysis and integrated, stepwise, mass-isotopomeric flux analysis (MIMOSA).ResultsNLRX1 KO significantly increased IRI (infarct size from 63% to 73%, end-diastolic pressure from 59 mmHg to 75 mmHg, and rate-pressure-product recovery from 15% to 6%), following severe, but not mild, ischemia. The increased IRI in NLRX1 KO hearts was associated with depressed Akt signaling at early reperfusion; other survival pathways or inflammatory parameters were not affected. Metabolically, NLRX1 KO hearts displayed increased lactate production and glucose oxidation relative to fatty acid oxidation, associated with increased pyruvate dehydrogenase flux and 10% higher cardiac oxygen consumption.ConclusionDeletion of the mitochondrially-located NOD-like sensor NLRX1 exacerbates severe cardiac IR injury, possibly through impaired Akt signaling, and increases cardiac glucose metabolism.

Project description:The persistent environmental aryl hydrocarbon receptor agonist and hepatotoxin TCDD (2,3,7,8-tetrachlorodibenzo- p -dioxin) induces hepatic lipid accumulation (steatosis), inflammation (steatohepatitis) and fibrosis. Thousands of liver-expressed, nuclear-localized lncRNAs with regulatory potential have been identified; however, their roles in TCDD-induced hepatoxicity and liver disease are unknown. We analyzed single nucleus (sn)RNA-seq data from control and chronic TCDD-exposed mouse liver to determine liver cell-type specificity, zonation and differential expression profiles for thousands of IncRNAs. TCDD dysregulated >4,000 of these lncRNAs in one or more liver cell types, including 684 lncRNAs specifically dysregulated in liver non-parenchymal cells. Trajectory inference analysis revealed major disruption by TCDD of hepatocyte zonation, affecting >800 genes, including 121 IncRNAs, with strong enrichment for lipid metabolism genes. TCDD also dysregulated expression of >200 transcription factors, including 19 Nuclear Receptors, most notably in hepatocytes and Kupffer cells. TCDD-induced changes in cellâ€"cell communication patterns included marked decreases in EGF signaling from hepatocytes to non-parenchymal cells and increases in extracellular matrix-receptor interactions central to liver fibrosis. Gene regulatory networks constructed from the snRNA-seq data identified TCDD-exposed liver network-essential lncRNA regulators linked to functions such as fatty acid metabolic process, peroxisome and xenobiotic metabolic. Networks were validated by the striking enrichments that predicted regulatory IncRNAs showed for specific biological pathways. These findings highlight the power of snRNA-seq to discover functional roles for many xenobiotic-responsive lncRNAs in both hepatocytes and liver non-parenchymal cells and to elucidate novel aspects of foreign chemical-induced hepatotoxicity and liver disease, including dysregulation of intercellular communication within the liver lobule.

Dataset Information

Zonation of nitrogen and glucose metabolism gene expression upon acute liver damage in mouse.

Publications

Zonation of nitrogen and glucose metabolism gene expression upon acute liver damage in mouse.

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