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Search Results: 1 - 10 of 27422 matches for " Robert Ehehalt "
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Overexpression of CD36 and Acyl-CoA Synthetases FATP2, FATP4 and ACSL1 Increases Fatty Acid Uptake in Human Hepatoma Cells
Julia Krammer, Margarete Digel, Friedrich Ehehalt, Wolfgang Stremmel, Joachim Füllekrug, Robert Ehehalt
International Journal of Medical Sciences , 2011,
Abstract: Background: Understanding the mechanisms of long chain fatty acid (LCFA) uptake in hepatic cells is of high medical importance to treat and to prevent fatty liver disease (FLD). ACSs (Acyl-CoA synthetases) are a family of enzymes that catalyze the esterification of fatty acids (FA) with CoA. Recent studies suggest that ACS enzymes drive the uptake of LCFA indirectly by their enzymatic activity and could promote special metabolic pathways dependent on their localization. The only protein located at the plasma membrane which has consistently been shown to enhance FA uptake is CD36. Aims: The current study investigated whether ACSs and CD36 could regulate hepatic LCFA uptake. Methods and Results: FATP2 and FATP4 were both localized to the ER of HuH7 and HepG2 cells as shown by double immunofluorescence in comparison to marker proteins. ACSL1 was located at mitochondria in both cell lines. Overexpression of FATP2, FATP4 and ACSL1 highly increased ACS activity as well as the uptake of [3H]-oleic acid and fluorescent Bodipy-C12 (B12) fatty acid. Quantitative FACS analysis showed a correlation between ACS expression levels and B12 uptake. FATP2 had the highest effect on B12 uptake of all proteins tested. CD36 was mainly localized at the plasma membrane. Whereas [3H]-oleic acid uptake was increased after overexpression, CD36 had no effect on B12 uptake. Conclusion: Uptake of LCFA into hepatoma cells can be regulated by the expression levels of intracellular enzymes. We propose that ACS enzymes drive FA uptake indirectly by esterification. Therefore these molecules are potential targets for treatment of nonalcoholic fatty liver disease (NAFLD) or steatohepatitis (NASH).
Overexpressed FATP1, ACSVL4/FATP4 and ACSL1 Increase the Cellular Fatty Acid Uptake of 3T3-L1 Adipocytes but Are Localized on Intracellular Membranes
Tianzuo Zhan, Margarete Poppelreuther, Robert Ehehalt, Joachim Füllekrug
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0045087
Abstract: Long chain acyl-CoA synthetases are essential enzymes of lipid metabolism, and have also been implicated in the cellular uptake of fatty acids. It is controversial if some or all of these enzymes have an additional function as fatty acid transporters at the plasma membrane. The most abundant acyl-CoA synthetases in adipocytes are FATP1, ACSVL4/FATP4 and ACSL1. Previous studies have suggested that they increase fatty acid uptake by direct transport across the plasma membrane. Here, we used a gain-of-function approach and established FATP1, ACSVL4/FATP4 and ACSL1 stably expressing 3T3-L1 adipocytes by retroviral transduction. All overexpressing cell lines showed increased acyl-CoA synthetase activity and fatty acid uptake. FATP1 and ACSVL4/FATP4 localized to the endoplasmic reticulum by confocal microscopy and subcellular fractionation whereas ACSL1 was found on mitochondria. Insulin increased fatty acid uptake but without changing the localization of FATP1 or ACSVL4/FATP4. We conclude that overexpressed acyl-CoA synthetases are able to facilitate fatty acid uptake in 3T3-L1 adipocytes. The intracellular localization of FATP1, ACSVL4/FATP4 and ACSL1 indicates that this is an indirect effect. We suggest that metabolic trapping is the mechanism behind the influence of acyl-CoA synthetases on cellular fatty acid uptake.
Molecular Pathogenesis of Pancreatic Neuroendocrine Tumors
Florian Ehehalt,Ellen Franke,Christian Pilarsky,Robert Grützmann
Cancers , 2010, DOI: 10.3390/cancers2041901
Abstract: Pancreatic neuroendocrine tumors (PNETs) are rare primary neoplasms of the pancreas and arise sporadically or in the context of genetically determined syndromes. Depending on hormone production and sensing, PNETs clinically manifest due to a hormone-related syndrome (functional PNET) or by symptoms related to tumor bulk effects (non-functional PNET). So far, radical surgical excision is the only therapy to cure the disease. Development of tailored non-surgical approaches has been impeded by the lack of experimental laboratory models and there is, therefore, a limited understanding of the complex cellular and molecular biology of this heterogeneous group of neoplasm. This review aims to summarize current knowledge of tumorigenesis of familial and sporadic PNETs on a cellular and molecular level. Open questions in the field of PNET research are discussed with specific emphasis on the relevance of disease management.
Lipid Based Therapy for Ulcerative Colitis—Modulation of Intestinal Mucus Membrane Phospholipids as a Tool to Influence Inflammation
Hannah Schneider,Annika Braun,Joachim Füllekrug,Wolfgang Stremmel,Robert Ehehalt
International Journal of Molecular Sciences , 2010, DOI: 10.3390/ijms11104149
Abstract: Ulcerative colitis (UC) is the result of an inappropriate colonic inflammatory response triggered by environmental and genetic factors. We have recently shown that mucus from UC patients has a decreased phosphatidylcholine (PC) content, while clinical trials revealed that therapeutic addition of PC to the colonic mucus alleviated the inflammatory activity. The mechanisms behind this are still unclear. We hypothesized that PC has at least two possible functions in the intestine: First, it establishes the surface hydrophobicity of the mucus and therefore protects the underlying tissue against intraluminal aggressors; recent experiments on surgical specimens revealed reduced surface tension and hydrophobicity in UC patients. Second, mucus phospholipids might also be integrated into the plasma membranes of enterocytes and thereby influence the signaling state of the mucosa. PC has been shown to inhibit TNF-α induced pro-inflammatory responses including: (1) assembly of plasma membrane actin; (2)?activation of MAP kinases ERK and p38; and (3) activation of NF-κB and synthesis of pro-inflammatory gene products. Other phospholipids like phosphatidylethanolamine or sphingomyelin ?had no effect. PC also inhibited latex bead phagosome actin assembly, killing of M. tuberculosis in macrophages, and sphingosine-1-phosphate induced actin assembly in macrophages. Collectively, these results provide a molecular foundation that shows PC, firstly, as an anti-inflammatory, and secondly, as a surface hydrophobicity increasing compound with promising therapeutic potential in the treatment of inflammatory bowel disease.
Transcript levels of different cytokines and chemokines correlate with clinical and endoscopic activity in ulcerative colitis
Alexandra Zahn, Thomas Giese, Max Karner, Annika Braun, Ulf Hinz, Wolfgang Stremmel, Robert Ehehalt
BMC Gastroenterology , 2009, DOI: 10.1186/1471-230x-9-13
Abstract: Cytokine and chemokine transcripts were quantified using real-time PCR in 49 mucosal biopsies from 27 different patients with UC. Cytokine transcript levels were correlated with CAI and EAI.There was a statistically significant positive correlation between CXCL8 (r = 0.30; p < 0.05), CXCL10 (r = 0.40; p < 0.02), calgranulin B (r = 0.36; p < 0.03), CXCL2 (r = 0.31; p < 0.05) and CAI. Concerning EAI significant positive correlations for CXCL8 (r = 0.37; p < 0.02), CXCL10 (r = 0.33; p < 0.04), calgranulin B (r = 0.31; p < 0.05) and CXCL2 (r = 0.44; p < 0.05) were found. Low clinical and endoscopic activity was accompanied by low cytokine levels whereas high CAI and EAI were associated with high cytokine levels.From our data, we conclude that real-time PCR quantification of CXCL8, CXCL10, calgranulin B and CXCL2 in colonic biopsies is a simple and objective method for grading inflammation of intestinal mucosa in UC. CXCL8, CXCL10, calgranulin B and CXCL2 might be used as biomarkers and thus as an objective tool especially in clinical trials to evaluate anti-inflammatory and immunomodulatory regimens.Inflammatory bowel disease (IBD) like ulcerative colitis (UC) and Crohn's disease (CD) are characterized by a relapsing and remitting clinical course. Disease activity and severity are variable and include both segmental processes with slight impairment of state of health and pancolitis with extensive gastrointestinal and systemic symptoms. Thus, the definition of disease activity in UC is often difficult. The clinical activity index (CAI) is only an indirect assessment tool of bowel inflammation and the endoscopic activity index (EAI) is sometimes unable to reflect the severity of disease to the full extent.Cytokine and chemokine mRNA expression profiles in UC have been characterized in former studies [1-3] and interleukin 8 (CXCL8), interferon γ inducible protein 10 (CXCL10), myeloid-related protein 14 (calgranulin B) and macrophage inflammatory protein 2 α (CXCL2) were id
Uptake of long chain fatty acids is regulated by dynamic interaction of FAT/CD36 with cholesterol/sphingolipid enriched microdomains (lipid rafts)
Robert Ehehalt, Richard Sparla, Hasan Kulaksiz, Thomas Herrmann, Joachim Füllekrug, Wolfgang Stremmel
BMC Cell Biology , 2008, DOI: 10.1186/1471-2121-9-45
Abstract: Dynamic association of FAT/CD36 a candidate fatty acid transporter with lipid rafts was analysed by isolation of detergent resistant membranes (DRMs) and by clustering of lipid rafts with antibodies on living cells. Lipid raft integrity was modulated by cholesterol depletion using methyl-β-cyclodextrin and sphingolipid depletion using myriocin and sphingomyelinase. Functional analyses were performed using an [3H]-oleate uptake assay.Overexpression of FAT/CD36 and FATP4 increased long chain fatty acid uptake. The uptake of long chain fatty acids was cholesterol and sphingolipid dependent. Floating experiments showed that there are two pools of FAT/CD36, one found in DRMs and another outside of these domains. FAT/CD36 co-localized with the lipid raft marker PLAP in antibody-clustered domains at the plasma membrane and segregated away from the non-raft marker GFP-TMD. Antibody cross-linking increased DRM association of FAT/CD36 and accelerated the overall fatty acid uptake in a cholesterol dependent manner. Another candidate transporter, FATP4, was neither present in DRMs nor co-localized with FAT/CD36 at the plasma membrane.Our observations suggest the existence of two pools of FAT/CD36 within cellular membranes. As increased raft association of FAT/CD36 leads to an increased fatty acid uptake, dynamic association of FAT/CD36 with lipid rafts might regulate the process. There is no direct interaction of FATP4 with lipid rafts or raft associated FAT/CD36. Thus, lipid rafts have to be considered as targets for the treatment of lipid disorders.Uptake of long chain fatty acids (LCFAs) is important for many cellular functions and the understanding of the uptake mechanisms is an important target for treatment of lipid disorders [1-4]. The molecular mechanisms of fatty acid transport across the plasma membrane are still a matter of debate and the predominating mechanism likely differs from cell to cell (for reviews see [5-8]). In general, two possible groups of mechanisms ar
Separate basolateral and apical phosphatidylcholine secretion routes in intestinally differentiated tumor cells
Daniel Gotthardt, Annika Braun, Anke Tietje, Karl Heinz Weiss, Robert Ehehalt, Wolfgang R Stremmel
World Journal of Gastroenterology , 2009,
Abstract: AIM: To investigate whether the secretion of phosphatidylcholine (PC) in intestinal mucus occurs by apical secretion or via basolateral excretion and to determine its subsequent passage across the tight junctions to the apical mucus.METHODS: We addressed this question using the polarized intestinally differentiated tumor cell line CaCo-2 grown on filters to confluence in Transwell culture chambers. The released PC and sphingomyelin (Sph) from apical and basolateral media were analyzed by mass spectrometry.RESULTS: The secreted PC species were identical in both compartments indicating the same intracellular origin of PC. However, PC secretion into the basolateral compartment was more effective, and the PC:Sph ratio in the basolateral compartment was significantly higher than that in the apical compartment (8.18 ± 1.84 vs 4.31 ± 1.22, P = 0.01). Both pathways were temperature sensitive and were unaltered in the presence of cyclosporine.CONCLUSION: The data demonstrate the PC secretion capacity of CaCo-2 cells and indicate two separated apical and basolateral release mechanisms.
Increased basolateral sorting of carcinoembryonic antigen in a polarized colon carcinoma cell line after cholesterol depletion-Implications for treatment of inflammatory bowel disease
Robert Ehehalt, Markus Krautter, Martin Zorn, Richard Sparla, Joachim Füllekrug, Hasan Kulaksiz, Wolfgang Stremmel
World Journal of Gastroenterology , 2008,
Abstract: AIM: To investigate a possible increase of basolateral expression of carcinoembryonic antigen (CEA) by interfering with the apical transport machinery, we studied the effect of cholesterol depletion on CEA sorting and secretion.METHODS: Cholesterol depletion was performed in polarized Caco-2 cells using lovastatin and methyl-β-cyclodextrin.RESULTS: We show that CEA is predominantly expressed and secreted at the apical surface. Reduction of the cholesterol level of the cell by 40%-50% with lovastatin and methyl-β-cyclodextrin led to a significant change of the apical-to-basolateral transport ratio towards the basolateral membrane.CONCLUSION: As basolateral expression of CEA has been suggested to have anti-inflammatory properties, Cholesterol depletion of enterocytes might be a potential approach to influence the course of inflammatory bowel disease.
TNF-α-induced up-regulation of pro-inflammatory cytokines is reduced by phosphatidylcholine in intestinal epithelial cells
Irina Treede, Annika Braun, Petia Jeliaskova, Thomas Giese, Joachim Füllekrug, Gareth Griffiths, Wolfgang Stremmel, Robert Ehehalt
BMC Gastroenterology , 2009, DOI: 10.1186/1471-230x-9-53
Abstract: PC species with different fatty acid side chains were applied to differentiated and non-differentiated Caco-2 cells treated with TNF-α to induce a pro-inflammatory response. We analysed TNF-α-induced NF-κB-activation via the transient expression of a NF-κB-luciferase reporter system. Pro-inflammatory gene transcription was detected with the help of a quantitative real time (RT)-PCR analysis. We assessed the binding of TNF-α to its receptor by FACS and analysed lipid rafts by isolating detergent resistant membranes (DRMs).The exogenous addition of all PC species tested significantly inhibited TNF-α-induced pro-inflammatory signalling. The expression levels of IL-8, ICAM-1, IP-10, MCP-1, TNF-α and MMP-1 were significantly reduced after PC pre-treatment for at least two hours. The effect was comparable to the inhibition of NF-kB by the NF-kB inhibitor SN 50 and was not due to a reduced binding of TNF-α to its receptor or a decreased surface expression of TNF-α receptors. PC was also effective when applied to the apical side of polarised Caco-2 cultures if cells were stimulated from the basolateral side. PC treatment changed the compartmentation of the TNF-α-receptors 1 and 2 to DRMs.PC induces a prolonged inhibition of TNF-α-induced pro-inflammatory signalling. This inhibition may be caused by a shift of the TNF-α receptors at the surface to lipid rafts. Our results may offer a potential molecular explanation for the positive role of PC seen in clinical studies for the treatment of ulcerative colitis.Inflammatory bowel disease (IBD) is the result of a chronic intestinal inflammatory response. While the exact pathogenesis of IBD remains incompletely understood, it is likely that the initiation of the immune response is triggered by luminal factors [1]. The nature of these initiating agents is unclear, but both orally ingested nutrients and microbial agents have been implicated [2]. It is widely believed that an impaired barrier function, and in particular a defect of th
Relativistic Transport Approach for Nucleus-Nucleus Collisions from SIS to SPS Energies
Wolfgang Ehehalt,Wolfgang Cassing
Physics , 1995, DOI: 10.1016/0375-9474(96)00097-8
Abstract: We formulate a covariant transport approach for high energy nucleus-nucleus collisions where the real part of the nucleon selfenergies is fitted to nuclear matter properties which are evaluated on the basis of a NJL-type Lagrangian for the quark degrees of freedom. The parameters of the quark-model Lagrangian are fixed by the Gell-Mann, Oakes and Renner relation, the pion- nucleon $\Sigma$-term, the nucleon energy as well as the nuclear binding energy at saturation density $\rho_0$. We find the resulting scalar and vector selfenergies for nucleons to be well in line with either Dirac-Brueckner computations for $\rho \leq 2 \rho_0$ or those from the phenomenological optical potential when accounting for a swelling of the nucleon at finite nuclear matter density. The meson-baryon interaction density is modelled to describe a decrease of the meson mass with baryon density. The imaginary part of the hadron selfenergies is determined by a string fragmentation model which accounts for the in-medium mass of hadrons in line with the 'chiral' dynamics employed. The applicability of the transport approach is demonstrated in comparison with experimental data from SIS to SPS energies. The enhancement of the K$^+/\pi^+$ ratio in A + A collisions compared to p + A reactions at AGS energies is reproduced within the 'chiral' dynamics. Furthermore, detailed predictions for the stopping in Pb + Pb collisions at 153 GeV/A are presented.
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