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Novel insights for cholesterol trafficking: detection and inhibition of hepatic inflammation

Projectomschrijving

Niet-alcoholische leververvetting is een leverziekte die voorkomt bij 1 op de 5 mensen in de Westerse samenleving. Bij een deel van deze mensen ontstaat na verloop van tijd leverontsteking, een chronische ziekte die ook wel bekend is als NASH. Met de bevindingen in dit project identificeerden wij nieuwe triggers die bijdragen aan het ontstaan van NASH. Op basis van deze triggers konden we ook nieuwe diagnostische en therapeutische aangrijpingspunten vinden om NASH te diagnosticeren en te behandelen. Zo identificeerden we verschillende componenten in het bloed die een afwijkende waarde hadden in NASH patiënten. Onze positieve bevindingen zullen nu gebruikt worden als basis voor verder klinisch onderzoek.

Producten

Titel: Macrophage Specific Caspase-1/11 Deficiency Protects against Cholesterol Crystallization and Hepatic Inflammation in Hyperlipidemic Mice
Auteur: Hendrikx, Tim, Bieghs, Veerle, Walenbergh, Sofie M. A., van Gorp, Patrick J., Verheyen, Fons, Jeurissen, Mike L. J., Steinbusch, Mandy M. F., Vaes, Nathalie, Binder, Christoph J., Koek, Ger H., Stienstra, Rinke, Netea, Mihai G., Hofker, Marten H., Shiri-Sverdlov, Ronit
Magazine: PLoS ONE
Titel: Cathepsin D regulates lipid metabolism in murine steatohepatitis
Auteur: Houben, Tom, Oligschlaeger, Yvonne, Hendrikx, Tim, Bitorina, Albert V., Walenbergh, Sofie M. A., van Gorp, Patrick J., Gijbels, Marion J. J., Friedrichs, Silvia, Plat, Jogchum, Schaap, Frank G., Lütjohann, Dieter, Hofker, Marten H., Shiri-Sverdlov, Ronit
Magazine: Scientific Reports
Titel: Hematopoietic overexpression of Cyp27a1 reduces hepatic inflammation independently of 27-hydroxycholesterol levels in Ldlr-/- mice
Auteur: Hendrikx, Tim, Jeurissen, Mike L.J., Bieghs, Veerle, Walenbergh, Sofie M.A., van Gorp, Patrick J., Verheyen, Fons, Houben, Tom, Guichot, Yasmin Dias, Gijbels, Marion J.J., Leitersdorf, Eran, Hofker, Marten H., Lütjohann, Dieter, Shiri-Sverdlov, Ronit
Magazine: Journal of Hepatology
Titel: Plasma cathepsin D correlates with histological classifications of fatty liver disease in adults and responds to intervention
Auteur: Walenbergh, Sofie M. A., Houben, Tom, Rensen, Sander S., Bieghs, Veerle, Hendrikx, Tim, van Gorp, Patrick J., Oligschlaeger, Yvonne, Jeurissen, Mike L. J., Gijbels, Marion J. J., Buurman, Wim A., Vreugdenhil, Anita C. E., Greve, Jan Willem M., Plat, Jogchum, Hofker, Marten H., Kalhan, Satish, Pihlajamäki, Jussi, Lindsey, Patrick, Koek, Ger H., Shiri-Sverdlov, Ronit
Magazine: Scientific Reports
Titel: Oxidized LDL at the crossroads of immunity in non-alcoholic steatohepatitis
Auteur: Houben, T., Brandsma, E., Walenbergh, S.M.A., Hofker, M.H., Shiri-Sverdlov, R.
Magazine: Biochimica et Biophysica Acta
Titel: Sialic Acid-Binding Immunoglobulin-like Lectin G Promotes Atherosclerosis and Liver Inflammation by Suppressing the Protective Functions of B-1 Cells
Auteur: Gruber, Sabrina, Hendrikx, Tim, Tsiantoulas, Dimitrios, Ozsvar-Kozma, Maria, Göderle, Laura, Mallat, Ziad, Witztum, Joseph L., Shiri-Sverdlov, Ronit, Nitschke, Lars, Binder, Christoph J.
Magazine: Cell Reports
Titel: Plasma IL-1 receptor antagonist levels correlate with the development of non-alcoholic steatohepatitis
Auteur: Hendrikx, Tim, Walenbergh, Sofie MA, Jeurissen, Mike LJ, Houben, Tom, van Gorp, Patrick J, Lindsey, Patrick J, Koek, Ger H, Kalhan, Satish, Pihlajamaki, Jussi, Hofker, Marten H, Shiri-Sverdlov, Ronit
Magazine: Biomarkers in Medicine
Titel: The immunity–diet–microbiota axis in the development of metabolic syndrome
Auteur: Brandsma, Eelke, Houben, Tom, Fu, Jingyuan, Shiri-Sverdlov, Ronit, Hofker, Marten H.
Magazine: Current Opinion in Lipidology
Titel: Macrophage Stimulating Protein Enhances Hepatic Inflammation in a NASH Model
Auteur: Li, Jieyi, Chanda, Dipanjan, van Gorp, Patrick J., Jeurissen, Mike L. J., Houben, Tom, Walenbergh, Sofie M. A., Debets, Jacques, Oligschlaeger, Yvonne, Gijbels, Marion J. J., Neumann, Dietbert, Shiri-Sverdlov, Ronit
Magazine: PLoS ONE
Titel: MSP is a negative regulator of inflammation and lipogenesis in ex vivo models of non-alcoholic steatohepatitis
Auteur: Chanda, Dipanjan, Li, Jieyi, Oligschlaeger, Yvonne, Jeurissen, Mike L J, Houben, Tom, Walenbergh, Sofie M A, Shiri-Sverdlov, Ronit, Neumann, Dietbert
Magazine: Experimental and Molecular Medicine
Titel: MSP: An emerging player in metabolic syndrome
Auteur: Li, Jieyi, Chanda, Dipanjan, Shiri-Sverdlov, Ronit, Neumann, Dietbert
Magazine: Cytokine Growth Factor Review
Titel: Low levels of IgM antibodies recognizing oxidation-specific epitopes are associated with human non-alcoholic fatty liver disease
Auteur: Hendrikx, Tim, Watzenböck, Martin L., Walenbergh, Sofie M. A., Amir, Shahzada, Gruber, Sabrina, Kozma, Maria Ozsvar, Grabsch, Heike I., Koek, Ger H., Pierik, Marieke J., Staufer, Katharina, Trauner, Michael, Kalhan, Satish C., Jonkers, Daisy, Hofker, Marten H., Binder, Christoph J., Shiri-Sverdlov, Ronit
Magazine: BMC Medicine
Titel: A novel approach to hepatitis: Unlocking the molecular secrets of the liver
Auteur: Ronit Shiri-Sverdlov
Magazine: International Innovation
Titel: Malondialdehyde epitopes are sterile mediators of hepatic inflammation in hypercholesterolemic mice
Auteur: Busch, Clara Jana-Lui, Hendrikx, Tim, Weismann, David, Jäckel, Sven, Walenbergh, Sofie M.A., Rendeiro, André F., Weißer, Juliane, Puhm, Florian, Hladik, Anastasiya, Göderle, Laura, Papac-Milicevic, Nikolina, Haas, Gerald, Millischer, Vincent, Subramaniam, Saravanan, Knapp, Sylvia, Bennett, Keiryn L., Bock, Christoph, Reinhardt, Christoph, Shiri-Sverdlov, Ronit, Binder, Christoph J.
Magazine: Hepatology
Titel: Bone marrow-specific caspase-1/11 deficiency inhibits atherosclerosis development in Ldlr -/- mice
Auteur: Hendrikx, Tim, Jeurissen, Mike L. J., van Gorp, Patrick J., Gijbels, Marion J., Walenbergh, Sofie M. A., Houben, Tom, van Gorp, Rick, Pöttgens, Chantal C., Stienstra, Rinke, Netea, Mihai G., Hofker, Marten H., Donners, Marjo M. P. C., Shiri-Sverdlov, Ronit
Magazine: FEBS Journal
Titel: Prevention of oxLDL uptake leads to decreased atherosclerosis in hematopoietic NPC1-deficient Ldlr-/- mice
Auteur: Jeurissen, Mike L.J., Walenbergh, Sofie M.A., Houben, Tom, Gijbels, Marion J.J., Li, Jieyi, Hendrikx, Tim, Oligschlaeger, Yvonne, van Gorp, Patrick J., Binder, Christoph J., Donners, Marjo M.P.C., Shiri-Sverdlov, Ronit
Magazine: Atherosclerosis
Titel: Niet-alcoholische vetleverziekte: multidisciplinaire uitdaging
Auteur: Koek Ger, Sofie Walenbergh, Ronit Shiri-Sverdlov
Magazine: MAGMA
Titel: Weekly Treatment of 2-Hydroxypropyl-ß-cyclodextrin Improves Intracellular Cholesterol Levels in LDL Receptor Knockout Mice
Auteur: Sofie M. A. Walenbergh, Tom Houben, Tim Hendrikx, Mike L. J. Jeurissen, Patrick J. van Gorp, Nathalie Vaes, Steven W. M. Olde Damink, Fons Verheyen, Ger H. Koek, Dieter Lütjohann, Alena Grebe, Eicke Latz and Ronit Shiri-Sverdlov
Titel: Lysosomal cholesterol accumulation: driver on the road to inflammation during atherosclerosis and non-alcoholic steatohepatitis
Auteur: Hendrikx, T., Walenbergh, S. M. A., Hofker, M. H., Shiri-Sverdlov, R.
Magazine: Obesity Reviews
Titel: Non-alcoholic steatohepatitis: The role of oxidized low-density lipoproteins
Auteur: Walenbergh, Sofie M.A., Koek, Ger H., Bieghs, Veerle, Shiri-Sverdlov, Ronit
Magazine: Journal of Hepatology
Titel: Cholesterol is a significant risk factor for non-alcoholic steatohepatitis
Auteur: Walenbergh, Sofie MA, Shiri-Sverdlov, Ronit
Magazine: Expert review of gastroenterology & hepatology
Titel: Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)
Auteur: Klionsky, Daniel J, Abdelmohsen, Kotb, Abe, Akihisa, Abedin, Md Joynal, Abeliovich, Hagai, Acevedo Arozena, Abraham, Adachi, Hiroaki, Adams, Christopher M, Adams, Peter D, Adeli, Khosrow, Adhihetty, Peter J, Adler, Sharon G, Agam, Galila, Agarwal, Rajesh, Aghi, Manish K, Agnello, Maria, Agostinis, Patrizia, Aguilar, Patricia V, Aguirre-Ghiso, Julio, Airoldi, Edoardo M, Ait-Si-Ali, Slimane, Akematsu, Takahiko, Akporiaye, Emmanuel T, Al-Rubeai, Mohamed, Albaiceta, Guillermo M, Albanese, Chris, Alb
Magazine: Autophagy
Titel: Anti-Inflammatory Pre-Treatment to Reduce Mobilization-Induced Liver Inflammation in Mice: Novel Model to Study Liver Injury
Auteur: Hendrikx, T., Piersma, C., Dhar, D. K., Mpabanzi, L., Schreurs, J. J. W., Malagó, M., Shiri-Sverdlov, R., Damink, S. W. M. Olde
Magazine: Modern Research in Inflammation
Titel: Weekly Treatment of 2-Hydroxypropyl-ß-cyclodextrin Improves Intracellular Cholesterol Levels in LDL Receptor Knockout Mice
Auteur: Walenbergh, Sofie, Houben, Tom, Hendrikx, Tim, Jeurissen, Mike, van Gorp, Patrick, Vaes, Nathalie, Damink, Steven, Verheyen, Fons, Koek, Ger, Lütjohann, Dieter, Grebe, Alena, Latz, Eicke, Shiri-Sverdlov, Ronit
Magazine: International Journal of Molecular Sciences
Titel: Myeloid DLL4 Does Not Contribute to the Pathogenesis of Non-Alcoholic Steatohepatitis in Ldlr-/- Mice
Auteur: Jeurissen, Mike L. J., Walenbergh, Sofie M. A., Houben, Tom, Hendrikx, Tim, Li, Jieyi, Oligschlaeger, Yvonne, van Gorp, Patrick J., Gijbels, Marion J. J., Bitorina, Albert, Nessel, Isabell, Radtke, Freddy, Vooijs, Marc, Theys, Jan, Shiri-Sverdlov, Ronit
Magazine: PLoS ONE
Titel: Plasma Cathepsin D Levels: A Novel Tool to Predict Pediatric Hepatic Inflammation
Auteur: Walenbergh, Sofie M A, Houben, Tom, Hendrikx, Tim, Jeurissen, Mike L J, van Gorp, Patrick J, Vreugdenhil, Anita C E, Adriaanse, Marlou P, Buurman, Wim A, Hofker, Marten H, Mosca, Antonella, Lindsey, Patrick J, Alisi, Anna, Liccardo, Daniela, Panera, Nadia, Koek, Ger H, Nobili, Valerio, Shiri-Sverdlov, Ronit
Magazine: American Journal of Gastroenterology
Titel: Protective Role of Plant Sterol and Stanol Esters in Liver Inflammation: Insights from Mice and Humans
Auteur: Plat, Jogchum, Hendrikx, Tim, Bieghs, Veerle, Jeurissen, Mike L. J., Walenbergh, Sofie M. A., van Gorp, Patrick J., De Smet, Els, Konings, Maurice, Vreugdenhil, Anita C. E., Guichot, Yasmin Dias, Rensen, Sander S., Buurman, Wim A., Greve, Jan Willem M., Lütjohann, Dieter, Mensink, Ronald P., Shiri-Sverdlov, Ronit
Magazine: PLoS ONE
Titel: The cholesterol derivative 27-hydroxycholesterol reduces steatohepatitis in mice
Auteur: Bieghs V, Hendrikx T, van Gorp PJ, Verheyen F, Guichot YD, Walenbergh SM, Jeurissen ML, Gijbels M, Rensen SS, Bast A, Plat J, Kalhan SC, Koek GH, Leitersdorf E, Hofker MH, Lütjohann D, Shiri-Sverdlov R
Magazine: Gastroenterology
Titel: Trapping of oxidized LDL in lysosomes of Kupffer cells is a trigger for hepatic inflammation
Auteur: Bieghs, Veerle, Walenbergh, Sofie M. A., Hendrikx, Tim, van Gorp, Patrick J., Verheyen, Fons, Olde Damink, Steven W., Masclee, Ad A., Koek, Ger H., Hofker, Marten H., Binder, Christoph J., Shiri-Sverdlov, Ronit
Magazine: Liver International
Titel: Blood-derived macrophages prone to accumulate lysosomal lipids trigger oxLDL-dependent murine hepatic inflammation
Auteur: Houben T, Oligschlaeger Y, Bitorina AV, Hendrikx T, Walenberg SMA, Lenders MH, Gijbels MJJ, Verheyen F, Lütjohann D, Hofker MH, Binder CJ, Shiri-Sverdlov R
Magazine: Scientific Reports
Titel: Young Investigator Award – Full bursary for the 48th Annual Meeting of the European Society of for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN), Amsterdam, the Netherlands
Titel: Conference grant by The Royal Netherlands Academy of Arts and Sciences (KNAW)
Titel: Award for Best Poster Presentation (1st price) at annual NUTRIM symposium, Maastricht, the Netherlands
Titel: Kootstra Postdoctoral Talent Fellowship
Titel: Award for Best Oral presentation (1st price) at the Dutch Liver Retreat, Spier, the Netherlands
Titel: Young Investigator Award – Waived registration bursary for the EASL International Liver Congress, Amsterdam, the Netherlands
Titel: EMBO Short Term Fellowship
Titel: Young Investigator Award – Full bursary for the EASL International Liver Congress, Vienna, Austria
Titel: Award for Best Poster Presentation at NVGE Voorjaarsvergadering, Veldhoven, the Netherlands
Titel: Boehringer Ingelheim Fonds Travel Grant
Titel: Award for Best Poster presentation (1st price) at the 1st European Fatty Liver Conference, Maastricht, the Netherlands
Titel: Young Hepatologist Award - Best Basic Science paper
Titel: Award for Best Poster Presentation (1st price) at the Plenary meeting, Department of Genetics and Cell Biology, Maastricht University Medical Center (MUMC), the Netherlands
Titel: Award for Best Poster Presentation at annual NUTRIM symposium, Maastricht, the Netherlands
Titel: Award for Best Pitch (1st price) at the Dutch Liver Retreat, Spier, the Netherlands
Titel: Awarded for Best Research Project Proposal “So you think you can heal the liver” at the Dutch Liver Retreat, Spier, the Netherlands
Titel: Conference grant from Universiteitsfonds Limburg/SWOL
Titel: Lysosomal lipid storage in blood-derived hepatic macrophages as trigger for hepatic inflammation
Auteur: Tom Houben
Titel: Storage solutions: targeting disturbed lysosomes to improve hepatic inflammation
Auteur: Ronit Shiri-Sverdlov as a last author
Titel: Targeting oxLDL to combat NPC1
Auteur: Ronit Shiri-Sverdlov as the last and presenting author
Titel: The inflammasome as a novel target for the detection and treatment of non-alcoholic steatohepatitis
Auteur: Ronit Shiri-Sverdlov as the last author Tim Hendrikx as the presenting author
Titel: Plasma cathepsin D: a novel marker for non-invasive diagnosis of non-alcoholic steatohepatitis
Auteur: Ronit Shiri-Sverdlov as a last author
Titel: Cellular gender identity - the inflammatory effects of 27-hydroxycholesterol are sex dependent
Auteur: A. Bitorina, M.L.J. Jeurissen, T. Houben, D.M. Meesters, S.M.A. Walenbergh, Y. Oligschlaeger, J. Plat, D. Lutjohann, A. Romano, R. Shiri-Sverdlov
Titel: Intracellular traffic jam in atherosclerosis and non-alcoholic steatohepatitis
Auteur: Ronit Shiri-Sverdlov as the last and presenting author
Titel: 27-Hydroxycholesterol: a potential treatment for non-alcoholic steatohepatitis in mice
Auteur: Ronit Shiri-Sverdlov as the last author
Titel: OxLDL is taking the lead in NASH
Auteur: Ronit Shiri-Sverdlov
Titel: Anti-oxLDL antibodies: a novel treatment for non-alcoholic steatohepatitis
Auteur: Ronit Shiri-Sverdlov as a last author
Titel: Plasma cathepsin D levels: a novel to predict pediatric hepatic inflammation
Auteur: Ronit Shiri-Sverdlov as a last author
Titel: Caspase-1 as novel target for the detection and treatment of non-alcoholic steatohepatitis
Auteur: Ronit Shiri-Sverdlov as a last author
Titel: Lysosomal cholesterol in Kupffer cells, particularly when oxidized, contributes to murine steatohepatitis
Auteur: Ronit Shiri-Sverdlov as a last author
Titel: The lysosomal enzyme cathepsin D as marker and therapeutic target for NASH
Auteur: Tom Houben
Titel: Trapping of oxidized LDL in lysosomes of Kupffer cells as a trigger for hepatic inflammation
Auteur: Ronit Shiri-Sverdlov as a last author
Titel: Plasma cathepsin D levels: a novel tool to predict pediatric hepatic inflammation
Auteur: Ronit Shiri-Sverdlov as the last author
Titel: Caspase-1 as a novel target for the detection and treatment of non-alcoholic steatohepatitis
Auteur: Ronit Shiri-Sverdlov as a last author
Titel: Cyp27: a novel player in diet-induced non-alcoholic steatohepatitis
Auteur: Ronit Shiri-Sverdlov as the last author Tim Hendrikx as the presenting author
Titel: 27-Hydroxycholesterol: a potential treatment for non-alcoholic steatohepatitis in mice
Auteur: Ronit Shiri-Sverdlov as a last author
Titel: The inflammasome: the role of hematopoetic caspase-1/11 in atherosclerosis development
Auteur: Ronit Shiri-Sverdlov as the last author Mike Jeurissen as the presenting author
Titel: Modulating plasma IgM autoantibodies in Niemann-Pick type C1 disease
Auteur: Yvonne Oligschlaeger
Titel: Lysosomes in motion: early non-invasive biomarkers for the detection of NASH
Auteur: Ronit Shiri-Sverdlov as last author Tom Houben as the presenting author
Titel: Cathepsin D: a novel way to improve diagnosis of non-alcoholic steatohepatitis
Auteur: Ronit Shiri-Sverdlov as a last author
Titel: OxLDL taking the lead in non-alcoholic steatohepatitis
Auteur: Ronit Shiri-Sverdlov as presenting, last author
Titel: Circulating cathepsin D regulates lipid metabolism in murine steatohepatitis
Auteur: Ronit Shiri-Sverdlov as a last author
Titel: Lysosomal cholesterol in plaque, particularly when oxidized, contributes to the development of atherosclerosis
Auteur: Ronit Shiri-Sverdlov as a last author
Titel: Caspase-1 as a novel target for the treatment of non-alcoholic steatohepatitis
Auteur: Ronit Shiri-Sverdlov as last author Tim Hendrikx as presenting author
Titel: The inflammasome as a novel target for the detection and treatment of non-alcoholic steatohepatitis
Auteur: Ronit Shiri-Sverdlov as a last author
Titel: Plasma cathepsin D levels: a novel tool to predict pediatric hepatic inflammation
Auteur: Ronit Shiri-Sverdlov as last author Sofie Walenbergh as presenting author
Titel: Exogenously Added Oxyphytosterols Do Not Play a Substantial Role in Macrophage-mediated Inflammation
Auteur: Yvonne Oligschlaeger, Tom Houben, Mike L.J. Jeurissen, Albert V. Bitorina, Maurice Konings, Sabine Baumgartner, Jogchum Plat, Ronit Shiri-Sverdlov
Titel: Streptococcus pneumoniae immunization as a complementary treatment for Niemann-Pick type C1
Auteur: T. Houben, A. Bitorina, Y. Oligschläger, M. Gijbels, T. Hendrikx, C. Binder, J. Prickaerts, R. Shiri-Sverdlov
Titel: Hematopoetic overexpression of CYP27A reduces hepatic inflammation, independently of 27HC levels in Ldlr-/- mice
Auteur: Ronit Shiri-Sverdlov as the last author Mike Jeurissen as the presenting author
Titel: Lysosomal enzymes: a novel non-invasive approach to detect hepatic inflammation in non-alcoholic steatohepatitis
Auteur: Ronit Shiri-Sverdlov as a last author
Titel: Protective effects of plant sterol and stanol esters in diet- induced non-alcoholic steatohepatitis in hyperlipidemic mice
Auteur: Ronit Shiri-Sverdlov as a last author
Titel: Lysosomal cholesterol in Kupffer cells, particularly when oxidized, contributes to murine steatohepatitis
Auteur: Ronit Shiri-Sverdlov as last author Sofie Walenbergh as presenting author
Titel: The lysosomal enzyme cathepsin D as a therapeutic target for NASH
Auteur: Tom Houben
Titel: Low levels of natural IgM antibodies towards oxidation-specific epitopes are associated with human non-alcoholic steatohepatitis
Auteur: Tim Hendrikx, Martin Watzenboeck, Sofie M. Walenbergh, Satish Kalhan, Ger H. Koek, Daisy Jonkers, Christoph J. Binder, Ronit Shiri-Sverdlov
Titel: Method for diagnosing pediatric NASH
Auteur: Shiri-Sverdlov R, Walenbergh SMA
Titel: Phytostanols for the prevention or treatment of hepatic inflammation.
Auteur: PLAT, Jogchum; SHIRI-SVERDLOV, Ronit; MENSINK, Ronald Peter; BIEGHS, Veerle
Titel: Method for the treatment of lysozomal lipid storage diseases
Auteur: SHIRI-SVERDLOV, R.
Titel: Method for treating liver inflammation, fibrosis and non-alcoholic steatohepatitis
Auteur: SHIRI-SVERDLOV, Ronit; BIEGHS, Veerle; GORP, VAN, Patrick Johannes Jacobus
Titel: Protein Purification: Principles and Trends
Auteur: Walenbergh SMA, Hendrikx T, Shiri-Sverdlov R
Titel: Research on Diabetes I
Auteur: Bieghs V, Shiri-Sverdlov R
Titel: Intracellular traffic jam: cholesterol accumulation as cause for chronic inflammatory diseases.
Auteur: T. Hendrikx
Titel: Lysosomes 'in control': where lipids meet inflammation in the metabolic syndrome
Auteur: Tom Houben
Titel: The entanglement of NASH and atherosclerosis - shared features of a macrophage-specific response
Auteur: M.L.J. Jeurissen
Titel: Storage solutions: novel ways for the detection and inhibition of non-alcoholic steatohepatitis (NASH).
Auteur: S.M.A. Walenbergh

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Samenvatting van de aanvraag

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is the hepatic event of the metabolic syndrome and is characterized by steatosis and inflammation. Whereas steatosis is harmless, the inflammatory component can lead to irreversible liver damage. However, the mechanisms by which inflammation is triggered are unknown. Consequently, therapeutic options are poor, non-invasive markers to detect NASH do not exist and the long-term burden to society is constantly increasing. Using a mouse model mimicking human NASH, I recently discovered that hepatic inflammation is associated with accumulation of oxidized cholesterol-rich low-density lipoproteins (oxLDL) in lysosomes of Kupffer cells and lysosomal dysfunction. Additionally, I also observed elevation of lysosomal enzymes in the plasma of patients with NASH. Under normal conditions, intracellular cholesterol is translocated from the lysosomes to the cytoplasm. However, when cholesterol is oxidized it accumulates in lysosomes and obstructs normal lysosomal function. Lysosomes play a major role in autophagy, a process by which cells degrade cellular components. Recent studies suggest that inhibition of autophagy activates the inflammasome, thereby triggering the maturation and release of pro-inflammatory cytokines. HYPOTHESIS: Lysosomal cholesterol accumulation in Kupffer cells results in inhibition of autophagy and activation of the inflammasome. OBJECTIVES: 1) Pathogenesis: investigate the mechanisms by which lysosomal cholesterol accumulation affects inflammation. The contribution of genes related to cholesterol trafficking, autophagy and inflammasome activation will be investigated selectively in Kupffer cells. 2) Diagnosis: establish non-invasive markers for hepatic inflammation. The levels of antibodies against oxLDL and lysosomal enzymes will be determined in plasma of patients showing a wide variety of fatty liver disease. 3) Therapy: identify novel treatment options for NASH, aimed at reducing lysosomal cholesterol accumulation in Kupffer cells. DELIVERABLES: 1) Provide a molecular understanding of the mechanisms triggering for hepatic inflammation. 2) Establish a new non-invasive diagnostic procedure for NASH. 3) Develop novel treatment options against NASH.

Onderwerpen

Kenmerken

Projectnummer:
91712327
Looptijd: 100%
Looptijd: 100 %
2012
2019
Gerelateerde subsidieronde:
Projectleider en penvoerder:
Dr. R. Sverdlov-Shiri
Verantwoordelijke organisatie:
Maastricht University Medical Centre+