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Human intestinal acyl-CoA synthetase 5 is sensitive to the inhibitor triacsin C

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World Journal of Gastroenterology 2011年第44期17卷 4883-4889页

作者： elke kaemmerer Anne Peuscher Andrea Reinartz Christian Liedtke Ralf Weiskirchen Jürgen Kopitz Nikolaus Gassler Department of Pediatrics RWTH Aachen UniversityAachenGermany Institute of Pathology RWTH Aachen University Department of Plant Biotechnology Fraunhofer Institute for Molecular Biology and Applied Ecology (IME) Institute of Pathology RWTH Aachen University Department of Medicine Ⅲ RWTH Aachen University Institute of Clinical Chemistry and Pathobiochemistry RWTH Aachen University Institute of Pathology University of Heidelberg

AIM:To investigate whether human acyl-CoA synthetase 5(ACSL5) is sensitive to the ACSL inhibitor triacsin ***:The ACSL isoforms ACSL1 and ACSL5 from rat as well as human ACSL5 were cloned and recombinantly expressed as 6xHis-tagged *** 2+-affinity purified recombinant enzymes were assayed at pH 7.5 or pH 9.5 in the presence or absence of triacsin *** addition,ACSL5 transfected CaCo2 cells and intestinal human mucosa were ***5 expression in cellular systems was verified using Western blot and *** ACSL assay mix included TrisHCl(pH 7.4),ATP,CoA,EDTA,DTT,MgCl 2,[9,103 H] palmitic acid,and triton *** 200 μL reaction was initiated with the addition of solubilized,purified recombinant proteins or cellular *** were terminated after 10,30 or 60 min of incubation with Doles ***:Expression of soluble recombinant ACSL proteins was found after incubation with isopropyl betaD-1-thiogalactopyranoside and after ultracentrifugation these were further purified to near homogeneity with Ni 2+-affinity *** C selectively and strongly inhibited recombinant human ACSL5 protein at pH 7.5 and pH 9.5,as well as recombinant rat ACSL1(sensitive control),but not recombinant rat ACSL5(insensitive control).The IC50 for human ACSL5 was about 10 μmol/*** inhibitory triacsin C effect was similar for different incubation times(10,30 and 60 min) and was not modified by the N-or C-terminal location of the *** order to evaluate ACSL5 sensitivity to triacsin C in a cellular environment,stable human ACSL5 CaCo2 transfectants and mechanically dissected normal human intestinal mucosa with high physiological expression of ACSL5 were *** both models,ACSL5 peak activity was found at pH 7.5 and pH 9.5,corresponding to the properties of recombinant human ACSL5 *** the presence of triacsin C(25 μmol/L),total ACSL activity was dramatically diminished in human ACSL5 transfectants as well as in AC

关键词：酰基辅酶A 肠道黏膜敏感性抑制剂合成酶重组表达亲和纯化 Triton

Fatty acid metabolism and acyl-CoA synthetases in the liver-gut axis

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World Journal of Hepatology 2021年第11期13卷 1512-1533页

作者： Yunxia Ma Miljana Nenkov Yuan Chen Adrian T Press elke kaemmerer Nikolaus Gassler Section Pathology Institute of Forensic MedicineJena University HospitalFriedrich Schiller University JenaJena 07747Germany Department of Anesthesiology and Intensive Care Medicine and Center for Sepsis Control and Care Jena University HospitalFriedrich Schiller University JenaJena 07747Germany Department of Pediatrics Jena University HospitalFriedrich Schiller University JenaJena 07747Germany

Fatty acids are energy substrates and cell components which participate in regulating signal transduction,transcription factor activity and secretion of bioactive lipid *** acyl-CoA synthetases(ACSs)family containing 26 family members exhibits tissue-specific distribution,distinct fatty acid substrate preferences and diverse biological *** evidence indicates that dysregulation of fatty acid metabolism in the liver-gut axis,designated as the bidirectional relationship between the gut,microbiome and liver,is closely associated with a range of human diseases including metabolic disorders,inflammatory disease and carcinoma in the gastrointestinal tract and *** this review,we depict the role of ACSs in fatty acid metabolism,possible molecular mechanisms through which they exert functions,and their involvement in hepatocellular and colorectal carcinoma,with particular attention paid to long-chain fatty acids and small-chain fatty ***,the liver-gut communication and the liver and gut intersection with the microbiome as well as diseases related to microbiota imbalance in the liver-gut axis are ***,the development of potentially therapeutic small molecules,proteins and compounds targeting ACSs in cancer treatment is summarized.

关键词： Long-chain fatty acids Short-chain fatty acids Acyl-CoA synthetases Microbiota Liver-gut axis

Intestinal acyl-CoA synthetase 5: Activation of long chain fatty acids and behind

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World Journal of Gastroenterology 2013年第42期19卷 7369-7373页

作者： Christina Klaus Min Kyung Jeon elke kaemmerer Nikolaus Gassler Institute of Pathology RWTH Aachen University52074 AachenGermany

The intestinal mucosa is characterized by a high complexity in terms of structure and functions and allows for a controlled demarcation towards the gut *** the one hand it is responsible for pulping and selective absorption of alimentary substances ensuring the immunological tolerance,on the other hand it prevents the penetration of micro-organisms as well as bacterial *** continuous regeneration of surface epithelia along the crypt-villus-axis in the small intestine is crucial to assuring these various *** core phenomena of intestinal epithelia regeneration comprise cell proliferation,migration,differentiation,and *** partly contrarily oriented processes are molecularly balanced through numerous interacting signaling pathways like Wnt/β-catenin,Notch and Hedgehog,and regulated by various modifying *** of these modifiers is acyl-CoA synthetase 5(ACSL5).It plays a key role in de novo lipid synthesis,fatty acid degradation and membrane modifications,and regulates several intestinal processes,primarily through different variants of protein lipidation,e.g.,***5 was shown to interact with proapoptotic molecules,and besides seems to inhibit proliferation along the *** of its proapoptotic and antiproliferative characteristics it could be of significant relevance for intestinal homeostasis,cellular disorder and tumor development.

关键词： Acyl-CoA synthetase Apoptosis Carcinogenesis Colorectal cancer Intestinal homeostasis

Molecular classification of colorectal carcinomas:The genotype-to-phenotype relation

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World Journal of Gastroenterology 2013年第45期19卷 8163-8167页

作者： elke kaemmerer Christina Klaus Min Kyung Jeon Nikolaus Gassler Institute of Pathology RWTH Aachen University 52074 Aachen Germany

Colorectal carcinomas(CRCs)are frequently found in industrialized countries and lead to a high incidence of malignancy-related *** by histomorphological features,CRCs and their pre-invasive lesions are quite *** underlying molecular mechanisms include genomic instability,genomic mutation of tumor suppressor genes or oncogenes,epigenetic changes,and the microRNA *** molecular mechanisms are guided by repeated clonal *** genotype-to-phenotype relation is assumed to be the great challenge of cancer research and the development of effective targeted *** present a strong genotype-to-phenotype relation is characterized only for a minority of ***,the molecular characterization of CRCs is essential to interpret histological patterns and to identify prognostic groups as well as patients for targeted therapy.

关键词： Carcinogenesis Colorectal cancer Molecular pathology

Coincidence of active Crohn's disease and florid endometriosis in the terminal ileum: A case report

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World Journal of Gastroenterology 2013年第27期19卷 4413-4417页

作者： elke kaemmerer Maren Westerkamp Reinhard Kasperk Gerhard Niepmann Axel Scherer Nikolaus Gassler Department of Pediatrics and Institute of Pathology RWTH Aachen University Department of Surgery Luisenhospital Aachen Department of Radiology Luisenhospital Aachen Institute of Pathology RWTH Aachen University

Crohn's disease (CD), a variant of chronic inflammatory bowel disease, frequently affects the terminal ileum and coecal region. The clinical symptoms are often subtle and depend on the inflammatory activity of disease. In women of child-bearing age, florid intestinal endometriosis can simulate CD. Moreover, current pathophysiological concepts include intestinal endometriosis as a putative founder lesion for consecutive CD establishment. The report summarizes clinical and histomorphological data of a 35-year-old woman with the rare coincidence of florid intestinal endometriosis and CD both affecting the terminal ileum. The patient was suffering over 10 years from strong abdominal disorders including constipation, diarrhea, weight loss, and diffuse abdominal pain. In magnetic resonance imaging-Sellink, strong inflammation and intestinal obstruction of the terminal ileum were found. The laparoscopy revealed further evidence for existence of an inflammatory disease like CD, but brownish spots on the peritoneum were found indicative for endometriosis. Surgical resection of the terminal ileum and the coecal segment was performed followed by histopathological investigations. In transmural sections of the terminal ileum, histomorphological features of florid endometriosis intermingled with florid CD was found. The diagnostic findings were substantiated with a panel of immunohistological stainings. In conclusion, the findings demonstrate that florid endometriosis persists in florid CD lesions and the putative link between intestinal endometriosis and CD is more complex than previously assumed.

关键词： Crohn’s diseases Intestinal endometriosis Pathogenesis

Modulating effects of acyl-CoA synthetase 5-derived mitochondrial Wnt2B palmitoylation on intestinal Wnt activity

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World Journal of Gastroenterology 2014年第40期20卷 14855-14864页

作者： Christina Klaus Ursula Schneider Christian Hedberg Anke K Schütz Jürgen Bernhagen Herbert Waldmann Nikolaus Gassler elke kaemmerer Institute of Pathology RWTH Aachen University 52074 Aachen Germany Department of Chemical Biology Max Planck Institute of Molecular Physiology 44227 Dortmund Germany Department of Biochemistry and Molecular Cell Biology RWTH Aachen University 52074 Aachen Germany Department of Pediatrics RWTH Aachen University 52074 Aachen Germany

AIM:To investigate the role of acyl-CoA synthetase 5(ACSL5)activity in Wnt signaling in intestinal surface ***:Several cell lines were used to investigate the ACSL5-dependent expression and synthesis of Wnt2B,a mitochondrially expressed protein of the Wnt signaling *** activity was functionally assessed with a luciferase reporter ***5-related biochemical Wnt2B modifications were investigatedwith a modified acyl-exchange *** findings from the cell culture models were verified using an Apcmin/+mouse model as well as normal and neoplastic diseased human intestinal ***:In the presence of ACSL5,Wnt2B was unable to translocate into the nucleus and was enriched in mitochondria,which was paralleled by a significant decrease in Wnt ***5-dependent S-palmitoylation of Wnt2B was identified as a molecular reason for mitochondrial Wnt2B *** cell culture systems,a strong relation of ACSL5 expression,Wnt2B palmitoylation,and degree of malignancy were *** normal mucosa,the association of ACSL5 and Wnt2B was seen,but in intestinal neoplasias the mechanism was only rudimentarily ***:ACSL5 mediates antiproliferative activities via Wnt2B palmitoylation with diminished Wnt *** molecular pathway is probably relevant for intestinal homeostasis,overwhelmed by other pathways in carcinogenesis.

关键词： Acyl-CoA synthetases Wnt signaling Palmitoylation

Beta-7 integrin controls enterocyte migration in the small intestine

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World Journal of Gastroenterology 2015年第6期21卷 1759-1764页

作者： elke kaemmerer Paula Kuhn Ursula Schneider Thomas Clahsen Min Kyung Jeon Christina Klaus Julia Andruszkow Michael Hrer Sabine Ernst Angela Schippers Norbert Wagner Nikolaus Gassler Institute of Pathology RWTH Aachen University Department of Pediatrics RWTH Aachen University Department of Medical Statistics RWTH Aachen University

AIM:To hypothesize that beta-7 integrin affects cellularmigration of both,lymphocytes and ***:The nucleoside analog Brd U was ip injected in beta-7-deficient mice(C57BL/6-Itgbtmlcgn/J)of male gender and age-matched male C57BL/J J mice(wild type)4,20,or 40 h before *** total small intestine was isolated,dissected,and used for morphometrical *** U-positive epithelial cells were numbered in at least 15 hemi-crypts per duodenum,jejunum,and ileum of each *** outer most Brd U-positive cell(cellmax)was determined per hemi-crypt,numerically documented,and statistically ***:Integrins containing the beta-7-chain were exclusively expressed on *** the small intestinal mucosa of beta-7 integrin-deficient mice the number of intraepithelial lymphocytes was drastically ***,the Peyer’s patches of beta-7integrin-deficient mice appeared *** beta-7integrin-deficient mice the location of cellmax was found in a higher position than it was the case for the *** difference was already detected at 4 h after Brd U application,but significantly increased with time(40 h after Brd U injection)in all small intestinal segments investigated,i.e.,duodenum,jejunum,and *** of small intestinal enterocytes was different between the experimental groups measured by cellmax ***:The E-cadherin beta-7 integrin pathway probably controls migration of enterocytes within the small intestinal surface lining epithelial layer.

关键词： Barrier function Cell migration Inflammatory bowel

Intestinal genetic inactivation of caspase-8 diminishes migration of enterocytes

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World Journal of Gastroenterology 2015年第15期21卷 4499-4508页

作者： elke kaemmerer Paula Kuhn Ursula Schneider Min Kyung Jeon Christina Klaus Miriam Schiffer Danika Weisner Christian Liedtke J?rg J?kel Lieven Nils Kennes Ralf-Dieter Hilgers Norbert Wagner Nikolaus Gassler Institute of Pathology RWTH Aachen University Department of Pediatrics RWTH Aachen University Department of Medicine Ⅲ RWTH Aachen University Department of Medical Statistics RWTH Aachen University

AIM: To verify the hypothesis that caspase-8(Casp8), which regulates cellular apoptosis and necroptosis, is critically involved in enterocyte ***: Casp8-silenced Caco2 cells were used in migration assays. In addition, enterocyte-specific Casp8 heterozygous(Casp8+/?int) or homozygous knockout mice(Casp8?int) were generated by crossing genetically modified mice carrying lox P recombination sites in intron 2 and 4 of the murine Casp8 gene with transgenic animals expressing a cre-transgene under control of the villin promoter in a pure C57/BL6 genetic background. The nucleoside analog Brd U was injected i.p. in male Casp8+/?int and Casp8?int animals 4 h, 20 h, or 40 h before performing morphometric studies. Locations of anti-Brd U-immunostained cells(cellmax) in at least 50 hemi-crypts of 6 histoanatomically distinct intestinal mucosal regions were numbered and extracted for statistical procedures. For the mice cohort(n = 28), the walking distance of enterocytes was evaluated from cellmax within crypt(n = 57), plateau(n = 19), and villus(n = 172) positions, resulting in a total of 6838 observations. Data analysis was performed by fitting a three-level mixed effects modelto the ***: In cell culture experiments with Caco2 cells, Casp8 knockdown efficiency mediated by RNA interference on Casp8 transcripts was 80% controlled as determined by Western blotting. In the scratch assay, migration of Casp8-deleted Caco2 cells was significantly diminished when compared with controls(Casp8?scramble and Caco2). In Brd U-labeled Casp8?int mice, cellmax locations were found along the hemi-crypts in a lower position than it was for Casp8+/?int or control(cre-negative) animals. Statistical data analysis with a three-level mixed effects model revealed that in the six different intestinal locations(distinct segments of the small and large intestine), cell movement between the three mice groups differed widely. Especially in duodenal hemi-crypts, enterocyte movement w

关键词： Barrier function Caspase 8 Cell migration Inflammatory bowel disease Intestinal morphogenesis

Fatty acid binding receptors in intestinal physiology and pathophysiology

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World Journal of Gastrointestinal Pathophysiology 2010年第5期1卷 147-153页

作者： elke kaemmerer Patrick Plum Christina Klaus Ralf Weiskirchen Christian Liedtke Maximilian Adolf Angela Schippers Norbert Wagner Andrea Reinartz Nikolaus Gassler Department of Pediatrics RWTH Aachen University Institute of Pathology RWTH Aachen University Institute of Clinical Chemistry and Pathobio-chemistry RWTH Aachen University Department of Medicine Ⅲ RWTH AachenUniversity

Free fatty acids are essential dietary components and recognized as important molecules in the maintenance of cellular *** the last decade,the molecular pathways for free fatty acid sensing in the gastrointestinal tract have been further elucidated by molecular identification and functional characterization of fatty acid binding *** sensing molecules belong to the family of G proteincoupled *** the intestine,four important receptors have been described so *** differ in molecular structure,ligand specificity,expression pattern,and functional *** this review,an overview of intestinal fatty acid binding receptors and their role in intestinal physiology and pathophysiology is given.

关键词： G protein Intestine Free fatty acid Receptor