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1. An unbiased ranking of murine dietary models based on their proximity to human metabolic dysfunction-associated steatotic liver disease (MASLD)

Author

Vacca, Michele, Kamzolas, Ioannis, Harder, Lea Mørch, Oakley, Fiona, Trautwein, Christian, Hatting, Maximilian, Ross, Trenton, Bernardo, Barbara, Oldenburger, Anouk, Hjuler, Sara Toftegaard, Ksiazek, Iwona, Lindén, Daniel, Schuppan, Detlef, Rodriguez-Cuenca, Sergio, Tonini, Maria Manuela, Castañeda, Tamara R., Kannt, Aimo, Rodrigues, Cecília M. P., Cockell, Simon, Govaere, Olivier, Daly, Ann K., Allison, Michael, Honnens de Lichtenberg, Kristian, Kim, Yong Ook, Lindblom, Anna, Oldham, Stephanie, Andréasson, Anne-Christine, Schlerman, Franklin, Marioneaux, Jonathon, Sanyal, Arun, Afonso, Marta B., Younes, Ramy, Amano, Yuichiro, Friedman, Scott L., Wang, Shuang, Bhattacharya, Dipankar, Simon, Eric, Paradis, Valérie, Burt, Alastair, Grypari, Ioanna Maria, Davies, Susan, Driessen, Ann, Yashiro, Hiroaki, Pors, Susanne, Worm Andersen, Maja, Feigh, Michael, Yunis, Carla, Bedossa, Pierre, Stewart, Michelle, Cater, Heather L., Wells, Sara, Schattenberg, Jörn M., Anstee, Quentin M., Tiniakos, Dina, Perfield, James W., Petsalaki, Evangelia, Davidsen, Peter, and Vidal-Puig, Antonio

Published
2024
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3. Adipose tissue macrophage dysfunction is associated with a breach of vascular integrity in NASH

Author

Boesch, Markus, Lindhorst, Andreas, Feio-Azevedo, Rita, Brescia, Paola, Silvestri, Alessandra, Lannoo, Matthias, Deleus, Ellen, Jaekers, Joris, Topal, Halit, Topal, Baki, Ostyn, Tessa, Wallays, Marie, Smets, Lena, Van Melkebeke, Lukas, Härtlova, Anetta, Roskams, Tania, Bedossa, Pierre, Verbeek, Jef, Govaere, Olivier, Francque, Sven, Sifrim, Alejandro, Voet, Thierry, Rescigno, Maria, Gericke, Martin, Korf, Hannelie, and van der Merwe, Schalk

Published
2024
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5. Impact of PNPLA3 rs738409 Polymorphism on the Development of Liver-Related Events in Patients With Nonalcoholic Fatty Liver Disease

Author

Rosso, Chiara, Caviglia, Gian Paolo, Birolo, Giovanni, Armandi, Angelo, Pennisi, Grazia, Pelusi, Serena, Younes, Ramy, Liguori, Antonio, Perez-Diaz-del-Campo, Nuria, Nicolosi, Aurora, Govaere, Olivier, Castelnuovo, Gabriele, Olivero, Antonella, Abate, Maria Lorena, Ribaldone, Davide Giuseppe, Fariselli, Piero, Valenti, Luca, Miele, Luca, Petta, Salvatore, Romero-Gomez, Manuel, Anstee, Quentin M., and Bugianesi, Elisabetta

Published
2023
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6. Performance of non-invasive tests and histology for the prediction of clinical outcomes in patients with non-alcoholic fatty liver disease: an individual participant data meta-analysis

Author

Anstee, Quentin M, Daly, Ann K, Govaere, Olivier, Cockell, Simon, Tiniakos, Dina, Bedossa, Pierre, Burt, Alastair, Oakley, Fiona, Cordell, Heather J, Day, Christopher P, Wonders, Kristy, Missier, Paolo, McTeer, Matthew, Vale, Luke, Oluboyede, Yemi, Breckons, Matt, Bossuyt, Patrick M, Zafarmand, Hadi, Vali, Yasaman, Lee, Jenny, Nieuwdorp, Max, Holleboom, Adriaan G, Verheij, Joanne, Ratziu, Vlad, Clément, Karine, Patino-Navarrete, Rafael, Pais, Raluca, Paradis, Valerie, Schuppan, Detlef, Schattenberg, Jörn M, Surabattula, Rambabu, Myneni, Sudha, Straub, Beate K, Vidal-Puig, Toni, Vacca, Michele, Rodrigues-Cuenca, Sergio, Allison, Mike, Kamzolas, Ioannis, Petsalaki, Evangelia, Campbell, Mark, Lelliott, Chris J, Davies, Susan, Orešič, Matej, Hyötyläinen, Tuulia, McGlinchey, Aiden, Mato, Jose M, Millet, Óscar, Dufour, Jean-François, Berzigotti, Annalisa, Masoodi, Mojgan, Pavlides, Michael, Harrison, Stephen, Neubauer, Stefan, Cobbold, Jeremy, Mozes, Ferenc, Akhtar, Salma, Olodo-Atitebi, Seliat, Banerjee, Rajarshi, Kelly, Matt, Shumbayawonda, Elizabeth, Dennis, Andrea, Andersson, Anneli, Wigley, Ioan, Romero-Gómez, Manuel, Gómez-González, Emilio, Ampuero, Javier, Castell, Javier, Gallego-Durán, Rocío, Fernández, Isabel, Montero-Vallejo, Rocío, Karsdal, Morten, Rasmussen, Daniel Guldager Kring, Leeming, Diana Julie, Sinisi, Antonia, Musa, Kishwar, Sandt, Estelle, Tonini, Manuela, Bugianesi, Elisabetta, Rosso, Chiara, Armandi, Angelo, Marra, Fabio, Gastaldelli, Amalia, Svegliati, Gianluca, Boursier, Jérôme, Francque, Sven, Vonghia, Luisa, Driessen, Ann, Ekstedt, Mattias, Kechagias, Stergios, Yki-Järvinen, Hannele, Porthan, Kimmo, Arola, Johanna, van Mil, Saskia, Papatheodoridis, George, Cortez-Pinto, Helena, Rodrigues, Cecilia M P, Valenti, Luca, Pelusi, Serena, Petta, Salvatore, Pennisi, Grazia, Miele, Luca, Geier, Andreas, Trautwein, Christian, Reißing, Johanna, Aithal, Guruprasad P, Francis, Susan, Palaniyappan, Naaventhan, Bradley, Christopher, Hockings, Paul, Schneider, Moritz, Newsome, Philip, Hübscher, Stefan, Wenn, David, Rosenquist, Christian, Trylesinski, Aldo, Mayo, Rebeca, Alonso, Cristina, Duffin, Kevin, Perfield, James W, Chen, Yu, Yunis, Carla, Tuthill, Theresa, Harrington, Magdalena Alicia, Miller, Melissa, Chen, Yan, McLeod, Euan James, Ross, Trenton, Bernardo, Barbara, Schölch, Corinna, Ertle, Judith, Younes, Ramy, Oldenburger, Anouk, Coxson, Harvey, Ostroff, Rachel, Alexander, Leigh, Biegel, Hannah, Kjær, Mette Skalshøi, Harder, Lea Mørch, Davidsen, Peter, Ellegaard, Jens, Balp, Maria-Magdalena, Brass, Clifford, Jennings, Lori, Martic, Miljen, Löffler, Jürgen, Applegate, Douglas, Shankar, Sudha, Torstenson, Richard, Lindén, Daniel, Fournier-Poizat, Céline, Llorca, Anne, Kalutkiewicz, Michael, Pepin, Kay, Ehman, Richard, Horan, Gerald, Ho, Gideon, Tai, Dean, Chng, Elaine, Patterson, Scott D, Billin, Andrew, Doward, Lynda, Twiss, James, Thakker, Paresh, Derdak, Zoltan, Landgren, Henrik, Lackner, Carolin, Gouw, Annette, Hytiroglou, Prodromos, Mózes, Ferenc E, Lee, Jenny A, Alzoubi, Osama, Staufer, Katharina, Trauner, Michael, Paternostro, Rafael, Stauber, Rudolf E, van Dijk, Anne-Marieke, Mak, Anne Linde, de Saint Loup, Marc, Shima, Toshihide, Gaia, Silvia, Shalimar, Lupșor-Platon, Monica, Wong, Vincent Wai-Sun, Li, Guanlin, Wong, Grace Lai-Hung, Karlas, Thomas, Wiegand, Johannes, Sebastiani, Giada, Tsochatzis, Emmanuel, Liguori, Antonio, Yoneda, Masato, Nakajima, Atsushi, Hagström, Hannes, Akbari, Camilla, Hirooka, Masashi, Chan, Wah-Kheong, Mahadeva, Sanjiv, Rajaram, Ruveena, Zheng, Ming-Hua, George, Jacob, Eslam, Mohammed, Viganò, Mauro, Ridolfo, Sofia, Aithal, Guruprasad Padur, Lee, Dae Ho, Nasr, Patrik, Cassinotto, Christophe, de Lédinghen, Victor, Mendoza, Yuly P, Noureddin, Mazen, Truong, Emily, and Harrison, Stephen A

Published
2023
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7. Intestinal B cells license metabolic T-cell activation in NASH microbiota/antigen-independently and contribute to fibrosis by IgA-FcR signalling

Author

Kotsiliti, Elena, Leone, Valentina, Schuehle, Svenja, Govaere, Olivier, Li, Hai, Wolf, Monika J., Horvatic, Helena, Bierwirth, Sandra, Hundertmark, Jana, Inverso, Donato, Zizmare, Laimdota, Sarusi-Portuguez, Avital, Gupta, Revant, O’Connor, Tracy, Giannou, Anastasios D., Shiri, Ahmad Mustafa, Schlesinger, Yehuda, Beccaria, Maria Garcia, Rennert, Charlotte, Pfister, Dominik, Öllinger, Rupert, Gadjalova, Iana, Ramadori, Pierluigi, Rahbari, Mohammad, Rahbari, Nuh, Healy, Marc E., Fernández-Vaquero, Mirian, Yahoo, Neda, Janzen, Jakob, Singh, Indrabahadur, Fan, Chaofan, Liu, Xinyuan, Rau, Monika, Feuchtenberger, Martin, Schwaneck, Eva, Wallace, Sebastian J., Cockell, Simon, Wilson-Kanamori, John, Ramachandran, Prakash, Kho, Celia, Kendall, Timothy J., Leblond, Anne-Laure, Keppler, Selina J., Bielecki, Piotr, Steiger, Katja, Hofmann, Maike, Rippe, Karsten, Zitzelsberger, Horst, Weber, Achim, Malek, Nisar, Luedde, Tom, Vucur, Mihael, Augustin, Hellmut G., Flavell, Richard, Parnas, Oren, Rad, Roland, Pabst, Olivier, Henderson, Neil C., Huber, Samuel, Macpherson, Andrew, Knolle, Percy, Claassen, Manfred, Geier, Andreas, Trautwein, Christoph, Unger, Kristian, Elinav, Eran, Waisman, Ari, Abdullah, Zeinab, Haller, Dirk, Tacke, Frank, Anstee, Quentin M., and Heikenwalder, Mathias

Published
2023
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8. Sublethal necroptosis signaling promotes inflammation and liver cancer

Author

Vucur, Mihael, Ghallab, Ahmed, Schneider, Anne T., Adili, Arlind, Cheng, Mingbo, Castoldi, Mirco, Singer, Michael T., Büttner, Veronika, Keysberg, Leonie S., Küsgens, Lena, Kohlhepp, Marlene, Görg, Boris, Gallage, Suchira, Barragan Avila, Jose Efren, Unger, Kristian, Kordes, Claus, Leblond, Anne-Laure, Albrecht, Wiebke, Loosen, Sven H., Lohr, Carolin, Jördens, Markus S., Babler, Anne, Hayat, Sikander, Schumacher, David, Koenen, Maria T., Govaere, Olivier, Boekschoten, Mark V., Jörs, Simone, Villacorta-Martin, Carlos, Mazzaferro, Vincenzo, Llovet, Josep M., Weiskirchen, Ralf, Kather, Jakob N., Starlinger, Patrick, Trauner, Michael, Luedde, Mark, Heij, Lara R., Neumann, Ulf P., Keitel, Verena, Bode, Johannes G., Schneider, Rebekka K., Tacke, Frank, Levkau, Bodo, Lammers, Twan, Fluegen, Georg, Alexandrov, Theodore, Collins, Amy L., Nelson, Glyn, Oakley, Fiona, Mann, Derek A., Roderburg, Christoph, Longerich, Thomas, Weber, Achim, Villanueva, Augusto, Samson, Andre L., Murphy, James M., Kramann, Rafael, Geisler, Fabian, Costa, Ivan G., Hengstler, Jan G., Heikenwalder, Mathias, and Luedde, Tom

Published
2023
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9. Identification of Reduced ERAP2 Expression and a Novel HLA Allele as Components of a Risk Score for Susceptibility to Liver Injury Due to Amoxicillin-Clavulanate

Author

Nicoletti, Paola, Dellinger, Andrew, Li, Yi Ju, Barnhart, Huiman X., Chalasani, Naga, Fontana, Robert J., Odin, Joseph A., Serrano, Jose, Stolz, Andrew, Etheridge, Amy S., Innocenti, Federico, Govaere, Olivier, Grove, Jane I., Stephens, Camilla, Aithal, Guruprasad P., Andrade, Raul J., Bjornsson, Einar S., Daly, Ann K., Lucena, M. Isabel, and Watkins, Paul B.

Published
2023
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11. TOP-328-YI Single-nucleus RNA sequencing of the liver identifies predictive markers to corticosteroid treatment in patients with severe alcohol-related hepatitis

Author

Van Melkebeke, Lukas, primary, Boesch, Markus, additional, Korf, Hannelie, additional, Ostyn, Tessa, additional, Bihary, Dóra, additional, Wallays, Marie, additional, Feio-Azevedo, Rita, additional, Boeckx, Bram, additional, Smets, Lena, additional, Reekmans, Ann, additional, Colle, Isabelle, additional, Van Malenstein, Hannah, additional, Topal, Halit, additional, Jaekers, Joris, additional, Claus, Eveline, additional, Bonne, Lawrence, additional, Maleux, Geert, additional, Roskams, Tania, additional, Nevens, Frederik, additional, Lambrechts, Diether, additional, Govaere, Olivier, additional, van der Merwe, Schalk, additional, and Verbeek, Jef, additional

Published
2024
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12. OS-040-YI Claudin-1 is a mediator and therapeutic target of biliary fibrosis by modulating liver progenitor cell fate and signaling

Author

Zompo, Fabio Del, primary, Crouchet, Emilie, additional, Ostyn, Tessa, additional, Jühling, Frank, additional, Moehlin, Julien, additional, Roehlen, Natascha, additional, Andrews, Tallulah, additional, Nakib, Diana, additional, Perciani, Catia, additional, Chung, Sai, additional, Bader, Gary L., additional, Mcgilvray, Ian, additional, MacParland, Sonya, additional, Iacone, Roberto, additional, Teixeira, Geoffrey, additional, Heikenwälder, Mathias, additional, Govaere, Olivier, additional, Roskams, Tania, additional, Schuster, Catherine, additional, Mailly, Laurent, additional, and Baumert, Thomas, additional

Published
2024
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15. Increased serum miR-193a-5p during non-alcoholic fatty liver disease progression: Diagnostic and mechanistic relevance

Author

Clark, James, Cordell, Heather J., Darlay, Rebecca, Day, Christopher P., Hardy, Tim, Liu, Yang-Lin, Oakley, Fiona, Palmer, Jeremy, Queen, Rachel, Wonders, Kristy, Bossuyt, Patrick M., Holleboom, Adriaan G., Zafarmand, Hadi, Vali, Yasaman, Lee, Jenny, Clement, Karine, Pais, Raluca, Schuppan, Detlef, Allison, Michael, Cuenca, Sergio Rodriguez, Pellegrinelli, Vanessa, Vacca, Michele, Vidal-Puig, Antonio, Hyötyläinen, Tuulia, McGlinchey, Aidan, Orešič, Matej, Sen, Partho, Mato, Jose, Millet, Óscar, Dufour, Jean-Francois, Harrison, Stephen, Neubauer, Stefan, Pavlides, Michael, Mozes, Ferenc, Akhtar, Salma, Banerjee, Rajarshi, Kelly, Matt, Shumbayawonda, Elizabeth, Dennis, Andrea, Erpicum, Charlotte, Romero-Gomez, Manuel, Gallego-Durán, Rocío, Fernández, Isabel, Karsdal, Morten, Leeming, Diana, Fisker, Mette Juul, Erhardtsen, Elisabeth, Rasmussen, Daniel, Qvist, Per, Sinisi, Antonia, Sandt, Estelle, Tonini, Maria Manuela, Parola, Maurizio, Rosso, Chiara, Marra, Fabio, Gastaldelli, Amalia, Francque, Sven, Kechagias, Stergios, Yki-Järvinen, Hannele, Porthan, Kimmo, van Mil, Saskia, Papatheodoridis, George, Cortez-Pinto, Helena, Valenti, Luca, Petta, Salvatore, Miele, Luca, Geier, Andreas, Trautwein, Christian, Hockings, Paul, Newsome, Phil, Wenn, David, Pereira Rodrigues, Cecília Maria, Hanf, Rémy, Chaumat, Pierre, Rosenquist, Christian, Trylesinski, Aldo, Ortiz, Pablo, Duffin, Kevin, Yunis, Carla, Miller, Melissa, Tuthill, Theresa, Ertle, Judith, Younes, Ramy, Alexander, Leigh, Ostroff, Rachel, Kjær, Mette Skalshøi, Mikkelsen, Lars Friis, Brass, Clifford, Jennings, Lori, Balp, Maria-Magdalena, Martic, Miljen, Hanauer, Guido, Shankar, Sudha, Torstenson, Richard, Fournier, Céline, Ehman, Richard, Kalutkiewicz, Michael, Pepin, Kay, Myers, Joel, Shevell, Diane, Ho, Gideon, Landgren, Henrik, Myers, Rob, Doward, Lynda, Whalley, Diane, Twiss, James, Johnson, Katherine, Leary, Peter J., Govaere, Olivier, Barter, Matthew J., Charlton, Sarah H., Cockell, Simon J., Tiniakos, Dina, Zatorska, Michalina, Bedossa, Pierre, Brosnan, M. Julia, Cobbold, Jeremy F., Ekstedt, Mattias, Aithal, Guruprasad P., Clément, Karine, Schattenberg, Jörn M., Boursier, Jerome, Ratziu, Vlad, Bugianesi, Elisabetta, Anstee, Quentin M., and Daly, Ann K.

Published
2022
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16. Comparison of the single-cell and single-nucleus hepatic myeloid landscape within decompensated cirrhosis patients

Author

Van Melkebeke, Lukas, primary, Verbeek, Jef, additional, Bihary, Dora, additional, Boesch, Markus, additional, Boeckx, Bram, additional, Feio-Azevedo, Rita, additional, Smets, Lena, additional, Wallays, Marie, additional, Claus, Eveline, additional, Bonne, Lawrence, additional, Maleux, Geert, additional, Govaere, Olivier, additional, Korf, Hannelie, additional, Lambrechts, Diether, additional, and van der Merwe, Schalk, additional

Published
2024
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17. Serum ferritin levels can predict long-term outcomes in patients with metabolic dysfunction-associated steatotic liver disease

Author

Armandi, Angelo, Sanavia, Tiziana, Younes, Ramy, Caviglia, Gian Paolo, Rosso, Chiara, Govaere, Olivier, Liguori, Antonio, Francione, Paolo, Gallego-Duran, Rocio, Ampuero, Javier, Pennisi, Grazia, Aller, Rocio, Tiniakos, Dina, Burt, Alastair, David, Ezio, Vecchio, Fabio, Maggioni, Marco, Cabibi, Daniela, Mcleod, Duncan, Pareja, Maria Jesus, Zaki, Marco Y. W., Stal, Per, Kechagias, Stergios, Fracanzani, Anna Ludovica, Valenti, Luca, Grieco, Antonio, Miele, Luca, Fariselli, Piero, Eslam, Mohammed, Petta, Salvatore, Hagstroem, Hannes, George, Jacob, Schattenberg, Joern M., Romero-Gomez, Manuel, Anstee, Quentin Mark, Bugianesi, Elisabetta, Armandi, Angelo, Sanavia, Tiziana, Younes, Ramy, Caviglia, Gian Paolo, Rosso, Chiara, Govaere, Olivier, Liguori, Antonio, Francione, Paolo, Gallego-Duran, Rocio, Ampuero, Javier, Pennisi, Grazia, Aller, Rocio, Tiniakos, Dina, Burt, Alastair, David, Ezio, Vecchio, Fabio, Maggioni, Marco, Cabibi, Daniela, Mcleod, Duncan, Pareja, Maria Jesus, Zaki, Marco Y. W., Stal, Per, Kechagias, Stergios, Fracanzani, Anna Ludovica, Valenti, Luca, Grieco, Antonio, Miele, Luca, Fariselli, Piero, Eslam, Mohammed, Petta, Salvatore, Hagstroem, Hannes, George, Jacob, Schattenberg, Joern M., Romero-Gomez, Manuel, Anstee, Quentin Mark, and Bugianesi, Elisabetta

Abstract

Objective Hyperferritinaemia is associated with liver fibrosis severity in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), but the longitudinal implications have not been thoroughly investigated. We assessed the role of serum ferritin in predicting long-term outcomes or death. Design We evaluated the relationship between baseline serum ferritin and longitudinal events in a multicentre cohort of 1342 patients. Four survival models considering ferritin with confounders or non-invasive scoring systems were applied with repeated five-fold cross-validation schema. Prediction performance was evaluated in terms of Harrell's C-index and its improvement by including ferritin as a covariate. Results Median follow-up time was 96 months. Liver-related events occurred in 7.7%, hepatocellular carcinoma in 1.9%, cardiovascular events in 10.9%, extrahepatic cancers in 8.3% and all-cause mortality in 5.8%. Hyperferritinaemia was associated with a 50% increased risk of liver-related events and 27% of all-cause mortality. A stepwise increase in baseline ferritin thresholds was associated with a statistical increase in C-index, ranging between 0.02 (lasso-penalised Cox regression) and 0.03 (ridge-penalised Cox regression); the risk of developing liver-related events mainly increased from threshold 215.5 mu g/L (median HR=1.71 and C-index=0.71) and the risk of overall mortality from threshold 272 mu g/L (median HR=1.49 and C-index=0.70). The inclusion of serum ferritin thresholds (215.5 mu g/L and 272 mu g/L) in predictive models increased the performance of Fibrosis-4 and Non-Alcoholic Fatty Liver Disease Fibrosis Score in the longitudinal risk assessment of liver-related events (C-indices>0.71) and overall mortality (C-indices>0.65). Conclusions This study supports the potential use of serum ferritin values for predicting the long-term prognosis of patients with MASLD., Funding Agencies|Italian Ministry for Education, University and Research (MIUR) [D15D18000410001]; PNRR M4C2I1.3 Heal Italia project [PE00000019 CUP B73C22001250006]; Ministry of Health [PNRR-MAD- 2022-12375656, RF- 2021-12372399, PRIN-2022 2022L273C9]; Robert W. Storr Bequest [RF- 2021-12374481]; National Health and Medical Research Council of Australia (NHMRC); Cancer Institute, NSW grant [APP1053206, APP2001692, APP1107178, APP1108422, APP1196492]; [2021/ATRG2028]

Published
2024
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18. NASH limits anti-tumour surveillance in immunotherapy-treated HCC

Author

Pfister, Dominik, Núñez, Nicolás Gonzalo, Pinyol, Roser, Govaere, Olivier, Pinter, Matthias, Szydlowska, Marta, Gupta, Revant, Qiu, Mengjie, Deczkowska, Aleksandra, Weiner, Assaf, Muller, Florian, Sinha, Ankit, Friebel, Ekaterina, Engleitner, Thomas, Lennggenhager, Daniela, Moncsek, Anja, and Heide, Danijela

Subjects
Fatty liver -- Complications and side effects, Immunotherapy -- Methods, Patient monitoring -- Methods, Hepatoma -- Care and treatment -- Causes of, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Hepatocellular carcinoma (HCC) can have viral or non-viral causes.sup.1-5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need.sup.6,7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8.sup.+PD1.sup.+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8.sup.+PD1.sup.+ T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8.sup.+PD1.sup.+CXCR6.sup.+, TOX.sup.+, and TNF.sup.+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8.sup.+ T cells or TNF neutralization, suggesting that CD8.sup.+ T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8.sup.+PD1.sup.+ T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment. In hepatocellular carcinoma driven by non-alcoholic steatohepatitis, aberrant T cell activation and impaired immune surveillance seem to make hepatocellular carcinoma less responsive to anti-PD1 or anti-PDL1 immunotherapy., Author(s): Dominik Pfister [sup.1] [sup.82] , Nicolás Gonzalo Núñez [sup.2] , Roser Pinyol [sup.3] , Olivier Govaere [sup.4] , Matthias Pinter [sup.5] [sup.6] , Marta Szydlowska [sup.1] , Revant Gupta [...]

Published
2021
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19. Spatial single-cell profiling of deeply matched extreme long-term surviving glioblastoma patients reveals a distinct immune and stem cell driven ecosystem

Author

Decraene, Brecht, primary, Antoranz, Asier, additional, Vanmechelen, Maxime, additional, Coppens, Grégoire, additional, Shankar, Gautam, additional, Spans, Lien, additional, Verbeke, Tatjana, additional, Solie, Lien, additional, Dubroja, Nikolina, additional, Nazari, Pouya, additional, Derweduwe, Marleen, additional, Sciot, Raf, additional, De Visser, Yanti, additional, Andhari, Madhavi, additional, Hecke, Manon Van, additional, Bempt, Isabelle Vanden, additional, Loon, Joannes van, additional, Agostinis, Patrizia, additional, Bamps, Sven, additional, Gijtenbeek, Anja, additional, Noens, Bonny, additional, Duerinck, Johnny, additional, De Mulder, Gert, additional, Weyns, Frank, additional, Broekman, Marike, additional, Govaere, Olivier, additional, Reuss, David E, additional, De Smet, Frederik, additional, and De Vleeschouwer, Steven, additional

Published
2024
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20. Serum ferritin levels can predict long-term outcomes in patients with metabolic dysfunction-associated steatotic liver disease

Author

Armandi, Angelo, primary, Sanavia, Tiziana, additional, Younes, Ramy, additional, Caviglia, Gian Paolo, additional, Rosso, Chiara, additional, Govaere, Olivier, additional, Liguori, Antonio, additional, Francione, Paolo, additional, Gallego-Duràn, Rocìo, additional, Ampuero, Javier, additional, Pennisi, Grazia, additional, Aller, Rocio, additional, Tiniakos, Dina, additional, Burt, Alastair, additional, David, Ezio, additional, Vecchio, Fabio, additional, Maggioni, Marco, additional, Cabibi, Daniela, additional, McLeod, Duncan, additional, Pareja, Maria Jesus, additional, Zaki, Marco Y W, additional, Grieco, Antonio, additional, Stål, Per, additional, Kechagias, Stergios, additional, Fracanzani, Anna Ludovica, additional, Valenti, Luca, additional, Miele, Luca, additional, Fariselli, Piero, additional, Eslam, Mohammed, additional, Petta, Salvatore, additional, Hagström, Hannes, additional, George, Jacob, additional, Schattenberg, Jörn M, additional, Romero-Gómez, Manuel, additional, Anstee, Quentin Mark, additional, and Bugianesi, Elisabetta, additional

Published
2024
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21. Adipose tissue macrophage dysfunction is associated with a breach of vascular integrity in NASH

Author

Boesch, Markus, primary, Lindhorst, Andreas, additional, Feio-Azevedo, Rita, additional, Brescia, Paola, additional, Silvestri, Alessandra, additional, Lannoo, Matthias, additional, Deleus, Ellen, additional, Jaekers, Joris, additional, Topal, Halit, additional, Topal, Baki, additional, Ostyn, Tessa, additional, Wallays, Marie, additional, Smets, Lena, additional, Van Melkebeke, Lukas, additional, Härtlova, Anetta, additional, Roskams, Tania, additional, Bedossa, Pierre, additional, Verbeek, Jef, additional, Govaere, Olivier, additional, Francque, Sven, additional, Sifrim, Alejandro, additional, Voet, Thierry, additional, Rescigno, Maria, additional, Gericke, Martin, additional, Korf, Hannelie, additional, and van der Merwe, Schalk, additional

Published
2023
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22. Key features of the environment promoting liver cancer in the absence of cirrhosis

Author

Zaki, Marco Youssef William, Mahdi, Ahmed Khairallah, Patman, Gillian Lucinda, Whitehead, Anna, Maurício, João Pais, McCain, Misti Vanette, Televantou, Despina, Abou-Beih, Sameh, Ramon-Gil, Erik, Watson, Robyn, Cox, Charlotte, Leslie, Jack, Wilson, Caroline, Govaere, Olivier, Lunec, John, Mann, Derek Austin, Nakjang, Sirintra, Oakley, Fiona, Shukla, Ruchi, Anstee, Quentin Mark, Tiniakos, Dina, and Reeves, Helen Louise

Published
2021
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23. Bone morphogenetic protein 8B promotes the progression of non-alcoholic steatohepatitis

Author

Vacca, Michele, Leslie, Jack, Virtue, Samuel, Lam, Brian Y. H., Govaere, Olivier, Tiniakos, Dina, Snow, Sophie, Davies, Susan, Petkevicius, Kasparas, Tong, Zhen, Peirce, Vivian, Nielsen, Mette Juul, Ament, Zsuzsanna, Li, Wei, Kostrzewski, Tomasz, Leeming, Diana Julie, Ratziu, Vlad, Allison, Michael E. D., Anstee, Quentin M., Griffin, Julian L., Oakley, Fiona, and Vidal-Puig, Antonio

Published
2020
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26. Serum levels of fibrogenesis biomarkers reveal distinct endotypes predictive of response to weight loss in advanced nonalcoholic fatty liver disease

Author

Karsdal, Morten A., primary, Hallsworth, Kate, additional, Scragg, Jadine, additional, Leeming, Diana J., additional, Villesen, Ida F., additional, Avery, Leah, additional, Haigh, Laura, additional, Govaere, Olivier, additional, Wichmann, Sarah, additional, Taylor, Guy, additional, Cassidy, Sophie, additional, McPherson, Stuart, additional, and Anstee, Quentin M., additional

Published
2023
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30. Impact of PNPLA3 rs738409 polymorphism on the development of liver-related events in patients with non-alcoholic fatty liver disease

Author

Rosso, Chiara, primary, Caviglia, Gian Paolo, additional, Birolo, Giovanni, additional, Armandi, Angelo, additional, Pennisi, Grazia, additional, Pelusi, Serena, additional, Younes, Ramy, additional, Liguori, Antonio, additional, Perez-Diaz-del-Campo, Nuria, additional, Nicolosi, Aurora, additional, Govaere, Olivier, additional, Castelnuovo, Gabriele, additional, Olivero, Antonella, additional, Abate, Maria Lorena, additional, Ribaldone, Davide Giuseppe, additional, Fariselli, Piero, additional, Valenti, Luca, additional, Miele, Luca, additional, Petta, Salvatore, additional, Romero-Gomez, Manuel, additional, Anstee, Quentin M., additional, and Bugianesi, Elisabetta, additional

Published
2023
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31. Corrigendum to: “Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically characterised cohort☆” [J Hepatol (2020) 505–515]

Author

Anstee, Quentin M., primary, Darlay, Rebecca, additional, Cockell, Simon, additional, Meroni, Marica, additional, Govaere, Olivier, additional, Tiniakos, Dina, additional, Burt, Alastair D., additional, Bedossa, Pierre, additional, Palmer, Jeremy, additional, Liu, Yang-Lin, additional, Aithal, Guruprasad P., additional, Allison, Michael, additional, Yki-Järvinen, Hannele, additional, Vacca, Michele, additional, Dufour, Jean-Francois, additional, Invernizzi, Pietro, additional, Prati, Daniele, additional, Ekstedt, Mattias, additional, Kechagias, Stergios, additional, Francque, Sven, additional, Petta, Salvatore, additional, Bugianesi, Elisabetta, additional, Clement, Karine, additional, Ratziu, Vlad, additional, Schattenberg, Jörn M., additional, Valenti, Luca, additional, Day, Christopher P., additional, Cordell, Heather J., additional, and Daly, Ann K., additional

Published
2023
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32. Correction: Genome-wide association study of non- alcoholic fatty liver and steatohepatitis in a histologically characterised cohort ( vol 73, pp 505-515 , 2020 )

Author

Anstee, Quentin M., Darlay, Rebecca, Cockell, Simon, Meroni, Marica, Govaere, Olivier, Tiniakos, Dina, Burt, Alastair D., Bedossa, Pierre, Palmer, Jeremy, Liu, Yang-Lin, Aithal, Guruprasad P., Allison, Michael, Yki-Jarvinen, Hannele, Vacca, Michele, Dufour, Jean-Francois, Invernizzi, Pietro, Prati, Daniele, Ekstedt, Mattias, Kechagias, Stergios, Francque, Sven, Petta, Salvatore, Bugianesi, Elisabetta, Clement, Karine, Ratziu, Vlad, Schattenberg, Joern M., Valenti, Luca, Day, Christopher P., Cordell, Heather J., Daly, Ann K., Anstee, Quentin M., Darlay, Rebecca, Cockell, Simon, Meroni, Marica, Govaere, Olivier, Tiniakos, Dina, Burt, Alastair D., Bedossa, Pierre, Palmer, Jeremy, Liu, Yang-Lin, Aithal, Guruprasad P., Allison, Michael, Yki-Jarvinen, Hannele, Vacca, Michele, Dufour, Jean-Francois, Invernizzi, Pietro, Prati, Daniele, Ekstedt, Mattias, Kechagias, Stergios, Francque, Sven, Petta, Salvatore, Bugianesi, Elisabetta, Clement, Karine, Ratziu, Vlad, Schattenberg, Joern M., Valenti, Luca, Day, Christopher P., Cordell, Heather J., and Daly, Ann K.

Abstract

Funding Agencies|Economic and Social Research Council

Published
2023
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33. Machine learning algorithm improves the detection of NASH (NAS-based) and at-risk NASH: A development and validation study

Author

Jenny, Lee, Max, Westphal, Yasaman, Vali, Jerome, Boursier, Salvatorre, Petta, Rachel, Ostroff, Leigh, Alexander, Yu, Chen, Celine, Fournier, Andreas, Geier, Sven, Francque, Kristy, Wonder, Dina, Tiniako, Pierre, Bedossa, Mike, Allison, Georgios, Papatheodoridi, Helena, Cortez-Pinto, Raluca, Pai, Jean-Francois, Dufour, Diana Julie, Leeming, Stephen, Harrison, Jeremy, Cobbold, Adriaan G, Holleboom, Hannele, Yki-Järvinen, Javier, Crespo, Mattias, Ekstedt, Guruprasad P, Aithal, Elisabetta, Bugianesi, Manuel, Romero-Gomez, Richard, Torstenson, Morten, Karsdal, Carla, Yuni, Jörn M, Schattenberg, Detlef, Schuppan, Vlad, Ratziu, Clifford, Bra, Kevin, Duffin, Koos, Zwinderman, Michael, Pavlide, Quentin M, Anstee, Patrick M, Bossuyt, Anstee, Quentin M., Daly, Ann K., Govaere, Olivier, Cockell, Simon, Tiniakos, Dina, Bedossa, Pierre, Burt, Alastair, Oakley, Fiona, Cordell, Heather J., Day, Christopher P., Wonders, Kristy, Missier, Paolo, Mcteer, Matthew, Vale, Luke, Oluboyede, Yemi, Breckons, Matt, Bossuyt, Patrick M., Zafarmand, Hadi, Vali, Yasaman, Lee, Jenny, Nieuwdorp, Max, Holleboom, Adriaan G., Verheij, Joanne, Ratziu, Vlad, Clément, Karine, Patino-Navarrete, Rafael, Pais, Raluca, Paradis, Valerie, Schuppan, Detlef, Schattenberg, Jörn M., Surabattula, Rambabu, Myneni, Sudha, Straub, Beate K., Vidal-Puig, Toni, Vacca, Michele, Rodrigues-Cuenca, Sergio, Allison, Mike, Kamzolas, Ioanni, Petsalaki, Evangelia, Campbell, Mark, Lelliott, Chris J., Davies, Susan, Orešič, Matej, Hyötyläinen, Tuulia, Mcglinchey, Aiden, Mato, Jose M., Millet, Óscar, Dufour, Jean-Françoi, Berzigotti, Annalisa, Masoodi, Mojgan, Pavlides, Michael, Harrison, Stephen, Neubauer, Stefan, Cobbold, Jeremy, Mozes, Ferenc, Akhtar, Salma, Olodo-Atitebi, Seliat, Banerjee, Rajarshi, Kelly, Matt, Shumbayawonda, Elizabeth, Dennis, Andrea, Andersson, Anneli, Wigley, Ioan, Romero-Gómez, Manuel, Gómez-González, Emilio, Ampuero, Javier, Castell, Javier, Gallego-Durán, Rocío, Fernández, Isabel, Montero-Vallejo, Rocío, Karsdal, Morten, Guldager Kring Rasmussen, Daniel, Leeming, Diana Julie, Sinisi, Antonia, Musa, Kishwar, Sandt, Estelle, Tonini, Manuela, Bugianesi, Elisabetta, Rosso, Chiara, Armandi, Angelo, Marra, Fabio, Gastaldelli, Amalia, Svegliati, Gianluca, Boursier, Jérôme, Francque, Sven, Vonghia, Luisa, Driessen, Ann, Ekstedt, Mattia, Kechagias, Stergio, Yki-Järvinen, Hannele, Porthan, Kimmo, Arola, Johanna, van Mil, Saskia, Papatheodoridis, George, Cortez-Pinto, Helena, Rodrigues, Cecilia M. P., Valenti, Luca, Pelusi, Serena, Petta, Salvatore, Pennisi, Grazia, Miele, Luca, Geier, Andrea, Trautwein, Christian, Aithal, Guruprasad P., Francis, Susan, Hockings, Paul, Schneider, Moritz, Newsome, Philip, Hübscher, Stefan, Wenn, David, Rosenquist, Christian, Trylesinski, Aldo, Mayo, Rebeca, Alonso, Cristina, Duffin, Kevin, Perfield, James W., Chen, Yu, Yunis, Carla, Tuthill, Theresa, Harrington, Magdalena Alicia, Miller, Melissa, Chen, Yan, Mcleod, Euan Jame, Ross, Trenton, Bernardo, Barbara, Schölch, Corinna, Ertle, Judith, Younes, Ramy, Oldenburger, Anouk, Ostroff, Rachel, Alexander, Leigh, Biegel, Hannah, Skalshøi Kjær, Mette, Mørch Harder, Lea, Davidsen, Peter, Mikkelsen, Lars Frii, Balp, Maria-Magdalena, Brass, Clifford, Jennings, Lori, Martic, Miljen, Löffler, Jürgen, Applegate, Dougla, Shankar, Sudha, Torstenson, Richard, Fournier-Poizat, Céline, Llorca, Anne, Kalutkiewicz, Michael, Pepin, Kay, Ehman, Richard, Horan, Gerald, Ho, Gideon, Tai, Dean, Chng, Elaine, Patterson, Scott D., Billin, Andrew, Doward, Lynda, Twiss, Jame, Thakker, Paresh, Landgren, Henrik, Lackner, Carolin, Gouw, Annette, Hytiroglou, Prodromos, Luca, Miele (ORCID:0000-0003-3464-0068), Jenny, Lee, Max, Westphal, Yasaman, Vali, Jerome, Boursier, Salvatorre, Petta, Rachel, Ostroff, Leigh, Alexander, Yu, Chen, Celine, Fournier, Andreas, Geier, Sven, Francque, Kristy, Wonder, Dina, Tiniako, Pierre, Bedossa, Mike, Allison, Georgios, Papatheodoridi, Helena, Cortez-Pinto, Raluca, Pai, Jean-Francois, Dufour, Diana Julie, Leeming, Stephen, Harrison, Jeremy, Cobbold, Adriaan G, Holleboom, Hannele, Yki-Järvinen, Javier, Crespo, Mattias, Ekstedt, Guruprasad P, Aithal, Elisabetta, Bugianesi, Manuel, Romero-Gomez, Richard, Torstenson, Morten, Karsdal, Carla, Yuni, Jörn M, Schattenberg, Detlef, Schuppan, Vlad, Ratziu, Clifford, Bra, Kevin, Duffin, Koos, Zwinderman, Michael, Pavlide, Quentin M, Anstee, Patrick M, Bossuyt, Anstee, Quentin M., Daly, Ann K., Govaere, Olivier, Cockell, Simon, Tiniakos, Dina, Bedossa, Pierre, Burt, Alastair, Oakley, Fiona, Cordell, Heather J., Day, Christopher P., Wonders, Kristy, Missier, Paolo, Mcteer, Matthew, Vale, Luke, Oluboyede, Yemi, Breckons, Matt, Bossuyt, Patrick M., Zafarmand, Hadi, Vali, Yasaman, Lee, Jenny, Nieuwdorp, Max, Holleboom, Adriaan G., Verheij, Joanne, Ratziu, Vlad, Clément, Karine, Patino-Navarrete, Rafael, Pais, Raluca, Paradis, Valerie, Schuppan, Detlef, Schattenberg, Jörn M., Surabattula, Rambabu, Myneni, Sudha, Straub, Beate K., Vidal-Puig, Toni, Vacca, Michele, Rodrigues-Cuenca, Sergio, Allison, Mike, Kamzolas, Ioanni, Petsalaki, Evangelia, Campbell, Mark, Lelliott, Chris J., Davies, Susan, Orešič, Matej, Hyötyläinen, Tuulia, Mcglinchey, Aiden, Mato, Jose M., Millet, Óscar, Dufour, Jean-Françoi, Berzigotti, Annalisa, Masoodi, Mojgan, Pavlides, Michael, Harrison, Stephen, Neubauer, Stefan, Cobbold, Jeremy, Mozes, Ferenc, Akhtar, Salma, Olodo-Atitebi, Seliat, Banerjee, Rajarshi, Kelly, Matt, Shumbayawonda, Elizabeth, Dennis, Andrea, Andersson, Anneli, Wigley, Ioan, Romero-Gómez, Manuel, Gómez-González, Emilio, Ampuero, Javier, Castell, Javier, Gallego-Durán, Rocío, Fernández, Isabel, Montero-Vallejo, Rocío, Karsdal, Morten, Guldager Kring Rasmussen, Daniel, Leeming, Diana Julie, Sinisi, Antonia, Musa, Kishwar, Sandt, Estelle, Tonini, Manuela, Bugianesi, Elisabetta, Rosso, Chiara, Armandi, Angelo, Marra, Fabio, Gastaldelli, Amalia, Svegliati, Gianluca, Boursier, Jérôme, Francque, Sven, Vonghia, Luisa, Driessen, Ann, Ekstedt, Mattia, Kechagias, Stergio, Yki-Järvinen, Hannele, Porthan, Kimmo, Arola, Johanna, van Mil, Saskia, Papatheodoridis, George, Cortez-Pinto, Helena, Rodrigues, Cecilia M. P., Valenti, Luca, Pelusi, Serena, Petta, Salvatore, Pennisi, Grazia, Miele, Luca, Geier, Andrea, Trautwein, Christian, Aithal, Guruprasad P., Francis, Susan, Hockings, Paul, Schneider, Moritz, Newsome, Philip, Hübscher, Stefan, Wenn, David, Rosenquist, Christian, Trylesinski, Aldo, Mayo, Rebeca, Alonso, Cristina, Duffin, Kevin, Perfield, James W., Chen, Yu, Yunis, Carla, Tuthill, Theresa, Harrington, Magdalena Alicia, Miller, Melissa, Chen, Yan, Mcleod, Euan Jame, Ross, Trenton, Bernardo, Barbara, Schölch, Corinna, Ertle, Judith, Younes, Ramy, Oldenburger, Anouk, Ostroff, Rachel, Alexander, Leigh, Biegel, Hannah, Skalshøi Kjær, Mette, Mørch Harder, Lea, Davidsen, Peter, Mikkelsen, Lars Frii, Balp, Maria-Magdalena, Brass, Clifford, Jennings, Lori, Martic, Miljen, Löffler, Jürgen, Applegate, Dougla, Shankar, Sudha, Torstenson, Richard, Fournier-Poizat, Céline, Llorca, Anne, Kalutkiewicz, Michael, Pepin, Kay, Ehman, Richard, Horan, Gerald, Ho, Gideon, Tai, Dean, Chng, Elaine, Patterson, Scott D., Billin, Andrew, Doward, Lynda, Twiss, Jame, Thakker, Paresh, Landgren, Henrik, Lackner, Carolin, Gouw, Annette, Hytiroglou, Prodromos, and Luca, Miele (ORCID:0000-0003-3464-0068)

Abstract

Background and aims: Detecting NASH remains challenging, while at-risk NASH (steatohepatitis and F≥ 2) tends to progress and is of interest for drug development and clinical application. We developed prediction models by supervised machine learning techniques, with clinical data and biomarkers to stage and grade patients with NAFLD. Approach and results: Learning data were collected in the Liver Investigation: Testing Marker Utility in Steatohepatitis metacohort (966 biopsy-proven NAFLD adults), staged and graded according to NASH CRN. Conditions of interest were the clinical trial definition of NASH (NAS ≥ 4;53%), at-risk NASH (NASH with F ≥ 2;35%), significant (F ≥ 2;47%), and advanced fibrosis (F ≥ 3;28%). Thirty-five predictors were included. Missing data were handled by multiple imputations. Data were randomly split into training/validation (75/25) sets. A gradient boosting machine was applied to develop 2 models for each condition: clinical versus extended (clinical and biomarkers). Two variants of the NASH and at-risk NASH models were constructed: direct and composite models.Clinical gradient boosting machine models for steatosis/inflammation/ballooning had AUCs of 0.94/0.79/0.72. There were no improvements when biomarkers were included. The direct NASH model produced AUCs (clinical/extended) of 0.61/0.65. The composite NASH model performed significantly better (0.71) for both variants. The composite at-risk NASH model had an AUC of 0.83 (clinical and extended), an improvement over the direct model. Significant fibrosis models had AUCs (clinical/extended) of 0.76/0.78. The extended advanced fibrosis model (0.86) performed significantly better than the clinical version (0.82). Conclusions: Detection of NASH and at-risk NASH can be improved by constructing independent machine learning models for each component, using only clinical predictors. Adding biomarkers only improved the accuracy of fibrosis.

Published
2023

34. Laminin-332 sustains chemoresistance and quiescence as part of the human hepatic cancer stem cell niche

Author

Govaere, Olivier, Wouters, Jasper, Petz, Michaela, Vandewynckel, Yves-Paul, Van den Eynde, Kathleen, Van den broeck, Anke, Verhulst, Stefaan, Dollé, Laurent, Gremeaux, Lies, Ceulemans, An, Nevens, Frederik, van Grunsven, Leo A., Topal, Baki, Vankelecom, Hugo, Giannelli, Gianluigi, Van Vlierberghe, Hans, Mikulits, Wolfgang, Komuta, Mina, and Roskams, Tania

Published
2016
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35. Higher Hepatic Glucose Production and Gluconeogenesis are Features of Severe Metabolic Dysfunction-Associated Steatohepatitis Even in Absence of T2D

Author

Sabatini, Silvia, primary, Sen, Partho, additional, Carli, Fabrizia, additional, Pezzica, Samantha, additional, Rosso, Chiara, additional, Lembo, Erminia, additional, Verrastro, Ornella, additional, Daly, Ann, additional, Govaere, Olivier, additional, Cockel, Simon, additional, Hyötyläinen, Tuulia, additional, Mingrone, Geltrude, additional, Bugianesi, Elisabetta, additional, Anstee, Quentin M., additional, Orešič, Matej, additional, and Gastaldelli, Amalia, additional

Published
2023
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38. Macrophage Scavenger Receptor 1 mediates lipid-induced inflammation in non-alcoholic fatty liver disease

Author

Govaere, Olivier, Kragh Petersen, Sine, Martinez-Lopez, Nuria, Wouters, Jasper, Van Haele, Matthias, Mancina, Rosellina M., Jamialahmadi, Oveis, Bilkei-Gorzo, Orsolya, Bel Lassen, Pierre, Darlay, Rebecca, Peltier, Julien, Palmer, Jeremy M., Younes, Ramy, Tiniakos, Dina, Aithal, Guruprasad P., Allison, Michael, Vacca, Michele, Berlinguer-Palmini, Rolando, Clark, James E., Drinnan, Michael J., Dufour, Jean-Francois, Ekstedt, Mattias, Francque, Sven, Petta, Salvatore, Bugianesi, Elisabetta, Day, Christopher P., Cordell, Heather J., Topal, Baki, Romeo, Stefano, Ratziu, Vlad, Roskams, Tania, Daly, Ann K., Anstee, Quentin M., and Trost, Matthias

Subjects
macrophages, immunometabolism, NASH, inflammation
Abstract

Background & Aims: Obesity-associated inflammation is a key player in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, the role of macrophage scavenger receptor 1 (MSR1, CD204) remains incompletely understood. Methods: 170 NAFLD liver biopsies were processed for transcriptomic analysis and correlated with clinicopathological features. Msr1-/- and WT mice were submitted to a 16 week high-fat and high-cholesterol diet. Therapeutic intervention with monoclonal antibody against MSR1 was performed in mice and ex vivo human liver slices. Genetic susceptibility was assessed using GWAS data from 1,483 NAFLD patients and 430,101 participants of the UKBiobank. Results: MSR1 expression was associated with the occurrence of hepatic lipid-laden foamy macrophages and correlated with the degree of steatosis and steatohepatitis in NAFLD patients. Mice lacking Msr1 were protected against diet-induced metabolic disorder, showing fewer hepatic foamy macrophages, less hepatic inflammation, improved dyslipidemia and glucose tolerance, while showing altered hepatic lipid metabolism. MSR1 induced a pro-inflammatory response via the JNK signalling pathway upon triggering by saturated fatty acids. In vitro blockade of the receptor prevented the accumulation of lipids in primary macrophages which inhibited the switch towards a pro-inflammatory phenotype and the release of cytokines such as TNF-?. Targeting MSR1 using monoclonal antibody therapy in an obesity-associated NAFLD mouse model and human liver slices resulted in the prevention of foamy macrophage formation and inflammation. Moreover, we identified that rs41505344, a polymorphism in the upstream transcriptional region of MSR1, was associated with altered serum triglycerides and aspartate transaminase levels in a cohort of over 400,000 patients. Conclusions: Taken together, our data suggest a critical role for MSR1 in lipid-induced inflammation and a potential therapeutic target for the treatment of NAFLD.

Published
2022

39. Performance of non-invasive tests and histology for the prediction of clinical outcomes in patients with non-alcoholic fatty liver disease: an individual participant data meta-analysis

Author

Mózes, Ferenc E, Lee, Jenny A, Vali, Yasaman, Alzoubi, Osama, Staufer, Katharina, Trauner, Michael, Paternostro, Rafael, Stauber, Rudolf E, Holleboom, Adriaan G, van Dijk, Anne-Marieke, Mak, Anne Linde, Boursier, Jérôme, de Saint Loup, Marc, Shima, Toshihide, Bugianesi, Elisabetta, Gaia, Silvia, Armandi, Angelo, Shalimar, Lupșor-Platon, Monica, Wong, Vincent Wai-Sun, Li, Guanlin, Wong, Grace Lai-Hung, Cobbold, Jeremy, Karlas, Thomas, Wiegand, Johannes, Sebastiani, Giada, Tsochatzis, Emmanuel, Liguori, Antonio, Yoneda, Masato, Nakajima, Atsushi, Hagström, Hannes, Akbari, Camilla, Hirooka, Masashi, Chan, Wah-Kheong, Mahadeva, Sanjiv, Rajaram, Ruveena, Zheng, Ming-Hua, George, Jacob, Eslam, Mohammed, Petta, Salvatore, Pennisi, Grazia, Viganò, Mauro, Ridolfo, Sofia, Aithal, Guruprasad Padur, Palaniyappan, Naaventhan, Lee, Dae Ho, Ekstedt, Mattias, Nasr, Patrik, Cassinotto, Christophe, de Lédinghen, Victor, Berzigotti, Annalisa, Mendoza, Yuly P, Noureddin, Mazen, Truong, Emily, Fournier-Poizat, Céline, Geier, Andreas, Martic, Miljen, Tuthill, Theresa, Anstee, Quentin M, Harrison, Stephen A, Bossuyt, Patrick M, Pavlides, Michael, Anstee, Quentin M, Daly, Ann K, Govaere, Olivier, Cockell, Simon, Tiniakos, Dina, Bedossa, Pierre, Burt, Alastair, Oakley, Fiona, Cordell, Heather J, Day, Christopher P, Wonders, Kristy, Missier, Paolo, McTeer, Matthew, Vale, Luke, Oluboyede, Yemi, Breckons, Matt, Bossuyt, Patrick M, Zafarmand, Hadi, Vali, Yasaman, Lee, Jenny, Nieuwdorp, Max, Holleboom, Adriaan G, Verheij, Joanne, Ratziu, Vlad, Clément, Karine, Patino-Navarrete, Rafael, Pais, Raluca, Paradis, Valerie, Schuppan, Detlef, Schattenberg, Jörn M, Surabattula, Rambabu, Myneni, Sudha, Straub, Beate K, Vidal-Puig, Toni, Vacca, Michele, Rodrigues-Cuenca, Sergio, Allison, Mike, Kamzolas, Ioannis, Petsalaki, Evangelia, Campbell, Mark, Lelliott, Chris J, Davies, Susan, Orešič, Matej, Hyötyläinen, Tuulia, McGlinchey, Aiden, Mato, Jose M, Millet, Óscar, Dufour, Jean-François, Berzigotti, Annalisa, Masoodi, Mojgan, Pavlides, Michael, Harrison, Stephen, Neubauer, Stefan, Cobbold, Jeremy, Mozes, Ferenc, Akhtar, Salma, Olodo-Atitebi, Seliat, Banerjee, Rajarshi, Kelly, Matt, Shumbayawonda, Elizabeth, Dennis, Andrea, Andersson, Anneli, Wigley, Ioan, Romero-Gómez, Manuel, Gómez-González, Emilio, Ampuero, Javier, Castell, Javier, Gallego-Durán, Rocío, Fernández, Isabel, Montero-Vallejo, Rocío, Karsdal, Morten, Rasmussen, Daniel Guldager Kring, Leeming, Diana Julie, Sinisi, Antonia, Musa, Kishwar, Sandt, Estelle, Tonini, Manuela, Bugianesi, Elisabetta, Rosso, Chiara, Armandi, Angelo, Marra, Fabio, Gastaldelli, Amalia, Svegliati, Gianluca, Boursier, Jérôme, Francque, Sven, Vonghia, Luisa, Driessen, Ann, Ekstedt, Mattias, Kechagias, Stergios, Yki-Järvinen, Hannele, Porthan, Kimmo, Arola, Johanna, van Mil, Saskia, Papatheodoridis, George, Cortez-Pinto, Helena, Rodrigues, Cecilia M P, Valenti, Luca, Pelusi, Serena, Petta, Salvatore, Pennisi, Grazia, Miele, Luca, Geier, Andreas, Trautwein, Christian, Reißing, Johanna, Aithal, Guruprasad P, Francis, Susan, Palaniyappan, Naaventhan, Bradley, Christopher, Hockings, Paul, Schneider, Moritz, Newsome, Philip, Hübscher, Stefan, Wenn, David, Rosenquist, Christian, Trylesinski, Aldo, Mayo, Rebeca, Alonso, Cristina, Duffin, Kevin, Perfield, James W, Chen, Yu, Yunis, Carla, Tuthill, Theresa, Harrington, Magdalena Alicia, Miller, Melissa, Chen, Yan, McLeod, Euan James, Ross, Trenton, Bernardo, Barbara, Schölch, Corinna, Ertle, Judith, Younes, Ramy, Oldenburger, Anouk, Coxson, Harvey, Ostroff, Rachel, Alexander, Leigh, Biegel, Hannah, Kjær, Mette Skalshøi, Harder, Lea Mørch, Davidsen, Peter, Ellegaard, Jens, Balp, Maria-Magdalena, Brass, Clifford, Jennings, Lori, Martic, Miljen, Löffler, Jürgen, Applegate, Douglas, Shankar, Sudha, Torstenson, Richard, Lindén, Daniel, Fournier-Poizat, Céline, Llorca, Anne, Kalutkiewicz, Michael, Pepin, Kay, Ehman, Richard, Horan, Gerald, Ho, Gideon, Tai, Dean, Chng, Elaine, Patterson, Scott D, Billin, Andrew, Doward, Lynda, Twiss, James, Thakker, Paresh, Derdak, Zoltan, Landgren, Henrik, Lackner, Carolin, Gouw, Annette, and Hytiroglou, Prodromos

Abstract

Histologically assessed liver fibrosis stage has prognostic significance in patients with non-alcoholic fatty liver disease (NAFLD) and is accepted as a surrogate endpoint in clinical trials for non-cirrhotic NAFLD. Our aim was to compare the prognostic performance of non-invasive tests with liver histology in patients with NAFLD.

Published
2023
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40. A meditarranean diet intervention has beneficial effects on biomarkers of cardiovascular risk and hepatic fibrosis in non-alcoholic fatty liver disease (NAFLD)

Author

Haigh, Laura, primary, Govaere, Olivier, additional, Brownlee, Lorna, additional, Charman, Sarah, additional, Blain, Alasdair, additional, Wilson, Thomas, additional, Karsdal, Morten, additional, Mcpherson, Stuart, additional, Mathers, John, additional, and Anstee, Quentin, additional

Published
2022
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42. Reprogramming necroptosis limits immune responses and prevents liver cancer development

Author

Vucur, Mihael, primary, Ghallab, Ahmed, additional, Schneider, Anne, additional, Kather, Jakob, additional, Govaere, Olivier, additional, Villanueva, Augusto, additional, Weber, Achim, additional, Longerich, Thomas, additional, Tacke, Frank, additional, Roderburg, Christoph, additional, Bode, Johannes, additional, Geisler, Fabian, additional, Neumann, Ulf, additional, Hengstler, Jan G., additional, Heikenwälder, Mathias, additional, and Lüdde, Tom, additional

Published
2022
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46. Is there a murine model that fully recapitulates human NASH? An unbiased bioinformatics approach to rank pre-clinical models based on proximity to human disease

Author

Vacca, Michele, primary, Kamzolas, Ioannis, additional, Harder, Lea Mørch, additional, Oakley, Fiona, additional, Trautwein, Christian, additional, Hatting, Maximilian, additional, Ross, Trenton, additional, Bernardo, Barbara, additional, Oldenburger, Anouk, additional, Hjuler, Sara Toftegaard, additional, Ksiazek, Iwona, additional, Linden, Daniel, additional, Schuppan, Detlef, additional, Rodriguez-Cuenca, Sergio, additional, Tonini, Maria Manuela, additional, Kannt, Aimo, additional, Rodriguez-Castaneda, Tamara, additional, Rodrigues, Cecília M.P, additional, Cockell, Simon, additional, Govaere, Olivier, additional, Daly, Ann K., additional, Allison, Michael, additional, de Lichtenberg, Kristian Honnens, additional, Kim, Yong Ook, additional, Lindblom, Anna, additional, Oldham, Stephanie, additional, Andréasson, Anne-Christine, additional, Schlerman, Franklin, additional, Marioneaux, Jonathon, additional, Sanyal, Arun, additional, Afonso, Marta B., additional, Rinaldi, Anthony, additional, Amano, Yuichiro, additional, Paradis, Valérie, additional, Burt, Alastair, additional, Susan, Davies, additional, Driessen, Ann, additional, Yashiro, Hiroaki, additional, Brosnan, M.Juli, additional, Yunis, Carla, additional, Bedossa, Pierre, additional, Tiniakos, Dina, additional, Anstee, Quentin, additional, Petsalaki, Evangelia, additional, Davidsen, Peter, additional, Perfield, Jim, additional, and Vidal-Puig, Antonio, additional

Published
2022
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47. Pharmacological testing of therapeutics using normothermic machine perfusion: A pilot study of 2,4‐dinitrophenol delivery to steatotic human livers

Author

Tingle, Samuel J., primary, Thompson, Emily R., additional, Bates, Lucy, additional, Ibrahim, Ibrahim K., additional, Govaere, Olivier, additional, Shuttleworth, Victoria, additional, Wang, Lu, additional, Figueiredo, Rodrigo, additional, Palmer, Jeremy, additional, Bury, Yvonne, additional, Anstee, Quentin M., additional, and Wilson, Colin, additional

Published
2022
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48. Increased serum miR-193a-5p during non-alcoholic fatty liver disease progression: Diagnostic and mechanistic relevance

Author

Johnson, Katherine, Leary, Peter J., Govaere, Olivier, Barter, Matthew J., Charlton, Sarah H., Cockell, Simon J., Tiniakos, Dina, Zatorska, Michalina, Bedossa, Pierre, Brosnan, M. Julia, Cobbold, Jeremy F., Ekstedt, Mattias, Aithal, Guruprasad P., Boursier, Jerome, Ratziu, Vlad, Bugianesi, Elisabetta, Anstee, Quentin M., Daly, Ann K., Clark, James, Cockell, Simon, Cordell, Heather J., Darlay, Rebecca, Day, Christopher P., Hardy, Tim, Liu, Yang-Lin, Oakley, Fiona, Palmer, Jeremy, Queen, Rachel, Wonders, Kristy, Bossuyt, Patrick M., Holleboom, Adriaan G., Zafarmand, Hadi, Vali, Yasaman, Lee, Jenny, Clement, Karine, Pais, Raluca, Schuppan, Detlef, Allison, Michael, Cuenca, Sergio Rodriguez, Pellegrinelli, Vanessa, Vacca, Michele, Vidal-Puig, Antonio, McGlinchey, Aidan, Sen, Partho, Mato, Jose, Dufour, Jean-Francois, Harrison, Stephen, Neubauer, Stefan, Pavlides, Michael, Mozes, Ferenc, Akhtar, Salma, Banerjee, Rajarshi, Kelly, Matt, Shumbayawonda, Elizabeth, Dennis, Andrea, Erpicum, Charlotte, Romero-Gomez, Manuel, Karsdal, Morten, Leeming, Diana, Fisker, Mette Juul, Erhardtsen, Elisabeth, Rasmussen, Daniel, Qvist, Per, Sinisi, Antonia, Sandt, Estelle, Tonini, Maria Manuela, Parola, Maurizio, Rosso, Chiara, Marra, Fabio, Gastaldelli, Amalia, Francque, Sven, Kechagias, Stergios, Porthan, Kimmo, van Mil, Saskia, Papatheodoridis, George, Cortez-Pinto, Helena, Valenti, Luca, Petta, Salvatore, Miele, Luca, Geier, Andreas, Trautwein, Christian, Hockings, Paul, Newsome, Phil, Wenn, David, Chaumat, Pierre, Rosenquist, Christian, Trylesinski, Aldo, Ortiz, Pablo, Duffin, Kevin, Yunis, Carla, Miller, Melissa, Tuthill, Theresa, Ertle, Judith, Younes, Ramy, Alexander, Leigh, Ostroff, Rachel, Mikkelsen, Lars Friis, Brass, Clifford, Jennings, Lori, Balp, Maria-Magdalena, Martic, Miljen, Hanauer, Guido, Shankar, Sudha, Torstenson, Richard, Ehman, Richard, Kalutkiewicz, Michael, Pepin, Kay, Myers, Joel, Shevell, Diane, Ho, Gideon, Landgren, Henrik, Myers, Rob, Doward, Lynda, Whalley, Diane, and Twiss, James

Subjects
Hepatology, Gastroenterology, Internal Medicine, Immunology and Allergy, digestive system diseases
Abstract

Background & Aims: Serum microRNA (miRNA) levels are known to change in non-alcoholic fatty liver disease (NAFLD) and may serve as useful biomarkers. This study aimed to profile miRNAs comprehensively at all NAFLD stages. Methods: We profiled 2,083 serum miRNAs in a discovery cohort (183 cases with NAFLD representing the complete NAFLD spectrum and 10 population controls). miRNA libraries generated by HTG EdgeSeq were sequenced by Illumina NextSeq. Selected serum miRNAs were profiled in 372 additional cases with NAFLD and 15 population controls by quantitative reverse transcriptase PCR. Results: Levels of 275 miRNAs differed between cases and population controls. Fewer differences were seen within individual NAFLD stages, but miR-193a-5p consistently showed increased levels in all comparisons. Relative to NAFL/non-alcoholic steatohepatitis (NASH) with mild fibrosis (stage 0/1), 3 miRNAs (miR-193a-5p, miR-378d, and miR378d) were increased in cases with NASH and clinically significant fibrosis (stages 2–4), 7 (miR193a-5p, miR-378d, miR-378e, miR-320b, miR-320c, miR-320d, and miR-320e) increased in cases with NAFLD activity score (NAS) 5–8 compared with lower NAS, and 3 (miR-193a-5p, miR-378d, and miR-378e) increased but 1 (miR-19b-3p) decreased in steatosis, activity, and fibrosis (SAF) activity score 2–4 compared with lower SAF activity. The significant findings for miR-193a-5p were replicated in the additional cohort with NAFLD. Studies in Hep G2 cells showed that following palmitic acid treatment, miR-193a-5p expression decreased significantly. Gene targets for miR-193a-5p were investigated in liver RNAseq data for a case subgroup (n = 80); liver GPX8 levels correlated positively with serum miR-193a-5p. Conclusions: Serum miR-193a-5p levels correlate strongly with NAFLD activity grade and fibrosis stage. MiR-193a-5p may have a role in the hepatic response to oxidative stress and is a potential clinically tractable circulating biomarker for progressive NAFLD. Lay summary: MicroRNAs (miRNAs) are small pieces of nucleic acid that may turn expression of genes on or off. These molecules can be detected in the blood circulation, and their levels in blood may change in liver disease including non-alcoholic fatty liver disease (NAFLD). To see if we could detect specific miRNA associated with advanced stages of NAFLD, we carried out miRNA sequencing in a group of 183 patients with NAFLD of varying severity together with 10 population controls. We found that a number of miRNAs showed changes, mainly increases, in serum levels but that 1 particular miRNA miR-193a-5p consistently increased. We confirmed this increase in a second group of cases with NAFLD. Measuring this miRNA in a blood sample may be a useful way to determine whether a patient has advanced NAFLD without an invasive liver biopsy.

Published
2022

49. Increased serum miR-193a-5p during non-alcoholic fatty liver disease progression: Diagnostic and mechanistic relevance

Author

Universidad de Sevilla. Departamento de Medicina, Johnson, Katherine, Leary, Peter J., Govaere, Olivier, Barter, Matthew J., Charlton, Sarah H., Cockell, Simon J., Romero Gómez, Manuel, Miller, Melissa, Universidad de Sevilla. Departamento de Medicina, Johnson, Katherine, Leary, Peter J., Govaere, Olivier, Barter, Matthew J., Charlton, Sarah H., Cockell, Simon J., Romero Gómez, Manuel, and Miller, Melissa

Abstract

Background & Aims Serum microRNA (miRNA) levels are known to change in non-alcoholic fatty liver disease (NAFLD) and may serve as useful biomarkers. This study aimed to profile miRNAs comprehensively at all NAFLD stages. Methods We profiled 2,083 serum miRNAs in a discovery cohort (183 cases with NAFLD representing the complete NAFLD spectrum and 10 population controls). miRNA libraries generated by HTG EdgeSeq were sequenced by Illumina NextSeq. Selected serum miRNAs were profiled in 372 additional cases with NAFLD and 15 population controls by quantitative reverse transcriptase PCR. Results Levels of 275 miRNAs differed between cases and population controls. Fewer differences were seen within individual NAFLD stages, but miR-193a-5p consistently showed increased levels in all comparisons. Relative to NAFL/non-alcoholic steatohepatitis (NASH) with mild fibrosis (stage 0/1), 3 miRNAs (miR-193a-5p, miR-378d, and miR378d) were increased in cases with NASH and clinically significant fibrosis (stages 2–4), 7 (miR193a-5p, miR-378d, miR-378e, miR-320b, miR-320c, miR-320d, and miR-320e) increased in cases with NAFLD activity score (NAS) 5–8 compared with lower NAS, and 3 (miR-193a-5p, miR-378d, and miR-378e) increased but 1 (miR-19b-3p) decreased in steatosis, activity, and fibrosis (SAF) activity score 2–4 compared with lower SAF activity. The significant findings for miR-193a-5p were replicated in the additional cohort with NAFLD. Studies in Hep G2 cells showed that following palmitic acid treatment, miR-193a-5p expression decreased significantly. Gene targets for miR-193a-5p were investigated in liver RNAseq data for a case subgroup (n = 80); liver GPX8 levels correlated positively with serum miR-193a-5p. Conclusions Serum miR-193a-5p levels correlate strongly with NAFLD activity grade and fibrosis stage. MiR-193a-5p may have a role in the hepatic response to oxidative stress and is a potential clinically tractable circulating biomarker for progressive NAFLD.

Published
2022

50. Metabolic signatures across the full spectrum of non-alcoholic fatty liver disease

Author

McGlinchey, Aidan J, Govaere, Olivier, Geng, Dawei, Ratziu, Vlad, Allison, Michael, Bousier, Jerome, Petta, Salvatore, de Oliviera, Claudia, Bugianesi, Elisabetta, Schattenberg, Jörn M., Daly, Ann K., Hyötyläinen, Tuulia, Anstee, Quentin M., Oresic, Matej, McGlinchey, Aidan J, Govaere, Olivier, Geng, Dawei, Ratziu, Vlad, Allison, Michael, Bousier, Jerome, Petta, Salvatore, de Oliviera, Claudia, Bugianesi, Elisabetta, Schattenberg, Jörn M., Daly, Ann K., Hyötyläinen, Tuulia, Anstee, Quentin M., and Oresic, Matej

Abstract

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is a progressive liver disease with potentially severe complications including cirrhosis and hepatocellular carcinoma. Previously, we have identified circulating lipid signatures associating with liver fat content and non-alcoholic steatohepatitis (NASH). Here, we develop a metabolomic map across the NAFLD spectrum, defining interconnected metabolic signatures of steatosis (non-alcoholic fatty liver, NASH, and fibrosis). Methods: We performed mass spectrometry analysis of molecular lipids and polar metabolites in serum samples from the European NAFLD Registry patients (n = 627), representing the full spectrum of NAFLD. Using various univariate, multivariate, and machine learning statistical approaches, we interrogated metabolites across 3 clinical perspectives: steatosis, NASH, and fibrosis. Results: Following generation of the NAFLD metabolic network, we identify 15 metabolites unique to steatosis, 18 to NASH, and 15 to fibrosis, with 27 common to all. We identified that progression from F2 to F3 fibrosis coincides with a key pathophysiological transition point in disease natural history, with n = 73 metabolites altered. Conclusions: Analysis of circulating metabolites provides important insights into the metabolic changes during NAFLD progression, revealing metabolic signatures across the NAFLD spectrum and features that are specific to NAFL, NASH, and fibrosis. The F2-F3 transition marks a critical metabolic transition point in NAFLD pathogenesis, with the data pointing to the pathophysiological importance of metabolic stress and specifically oxidative stress. Clinical Trials registration: The study is registered at Clinicaltrials.gov (NCT04442334). Lay summary: Non-alcoholic fatty liver disease is characterised by the build-up of fat in the liver, which progresses to liver dysfunction, scarring, and irreversible liver failure, and is markedly increasing in its prevalence worldwide. Here, we measure, Funding agencies:Elucidating Pathways of Steatohepatitis (EPoS) consortium - Horizon 2020634413Innovative Medicines Initiative (IMI2) Program of the European Union 777377EFPIANewcastle NIHR Biomedical Research CentreEuropean NAFLD Registry

Published
2022
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