Altered liver sinusoidal endothelial cells in MASLD and their evolution following lanifibranor treatment
Pierre-Emmanuel Rautou,
Shivani Chotkoe,
Louise Biquard,
Guillaume Wettstein,
Denise van der Graaff,
Yao Liu,
Joris De Man,
Christophe Casteleyn,
Sofie Thys,
Winnok H. De Vos,
Pierre Bedossa,
Michael P. Cooreman,
Martine Baudin,
Jean-Louis Abitbol,
Philippe Huot-Marchand,
Lucile Dzen,
Miguel Albuquerque,
Pierre Broqua,
Jean-Louis Junien,
Luisa Vonghia,
Manal F. Abdelmalek,
Wilhelmus J. Kwanten,
Valérie Paradis,
Sven M. Francque
Affiliations
Pierre-Emmanuel Rautou
Université Paris-Cité, Inserm, Centre de recherche sur l'inflammation, Paris, France; AP-HP, Hôpital Beaujon, Service d'Hépatologie, DMU DIGEST, Centre de Référence des Maladies Vasculaires du Foie, FILFOIE, ERN RARE-LIVER, Clichy, France; Corresponding authors. Addresses: Service d’Hépatologie, Hôpital Beaujon, 100 Boulevard du General Leclerc, 92100 Clichy, France. Tel.: +331 40 87 52 83; fax +331 40 87 44 35 (P-E. Rautou); Department of Gastroenterology and Hepatology, University Hospital Antwerp, Drie Eikenstraat 655, 2650 Edegem, Belgium. Tel.: +32 3 821 44 75 (S. Francque).
Shivani Chotkoe
Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium; Laboratory of Experimental Medicine and Paediatrics, University of Antwerp, Antwerp, Belgium
Louise Biquard
Université Paris-Cité, Inserm, Centre de recherche sur l'inflammation, Paris, France
Guillaume Wettstein
INVENTIVA, Daix, France and New York, NY, USA
Denise van der Graaff
Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium; Laboratory of Experimental Medicine and Paediatrics, University of Antwerp, Antwerp, Belgium
Yao Liu
Department of Hepatology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
Joris De Man
Laboratory of Experimental Medicine and Paediatrics, University of Antwerp, Antwerp, Belgium
Christophe Casteleyn
Department of Morphology, Imaging, Orthopedics, Rehabilitation and Nutrition, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium; Comparative Perinatal Development, Department of Veterinary Sciences, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Antwerp, Belgium
Sofie Thys
Laboratory of Cell Biology and Histology, University of Antwerp, Antwerp, Belgium; Antwerp Centre for Advanced Microscopy (ACAM), University of Antwerp, Antwerp, Belgium
Winnok H. De Vos
Laboratory of Cell Biology and Histology, University of Antwerp, Antwerp, Belgium; Antwerp Centre for Advanced Microscopy (ACAM), University of Antwerp, Antwerp, Belgium; μNEURO, Centre of Excellence, University of Antwerp, Antwerp, Belgium
Pierre Bedossa
Liverpat, Paris, France
Michael P. Cooreman
INVENTIVA, Daix, France and New York, NY, USA
Martine Baudin
INVENTIVA, Daix, France and New York, NY, USA
Jean-Louis Abitbol
INVENTIVA, Daix, France and New York, NY, USA
Philippe Huot-Marchand
INVENTIVA, Daix, France and New York, NY, USA
Lucile Dzen
INVENTIVA, Daix, France and New York, NY, USA
Miguel Albuquerque
Liverpat, Paris, France
Pierre Broqua
INVENTIVA, Daix, France and New York, NY, USA
Jean-Louis Junien
INVENTIVA, Daix, France and New York, NY, USA
Luisa Vonghia
Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium; Laboratory of Experimental Medicine and Paediatrics, University of Antwerp, Antwerp, Belgium
Manal F. Abdelmalek
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
Wilhelmus J. Kwanten
Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium; Laboratory of Experimental Medicine and Paediatrics, University of Antwerp, Antwerp, Belgium
Valérie Paradis
Université Paris-Cité, Inserm, Centre de recherche sur l'inflammation, Paris, France; AP-HP, Hôpital Beaujon, Department of Pathology, FHU MOSAIC, Clichy, France
Sven M. Francque
Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium; Laboratory of Experimental Medicine and Paediatrics, University of Antwerp, Antwerp, Belgium; Corresponding authors. Addresses: Service d’Hépatologie, Hôpital Beaujon, 100 Boulevard du General Leclerc, 92100 Clichy, France. Tel.: +331 40 87 52 83; fax +331 40 87 44 35 (P-E. Rautou); Department of Gastroenterology and Hepatology, University Hospital Antwerp, Drie Eikenstraat 655, 2650 Edegem, Belgium. Tel.: +32 3 821 44 75 (S. Francque).
Background & Aims: Data on changes in liver sinusoidal endothelial cells (LSECs) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and their response to treatment are limited. This study aimed at determining (i) features associated with LSEC capillarisation in patients with MASLD; (ii) whether LSEC changes can regress with the pan-peroxisome proliferator-activated receptor (PPAR) agonist lanifibranor; (iii) the role of the different PPAR isotypes on LSEC changes in MASLD. Methods: We analysed CD34 expression, a marker of LSEC capillarisation, on liver biopsies from patients considered for inclusion in the NATIVE trial at baseline (n = 249), and after 24 weeks of placebo or lanifibranor (n = 173). Two rat models of MASLD were used to investigate the effect of lanifibranor or of mono-PPAR agonists on LSECs. Results: Lobular CD34 staining was more intense in patients with isolated steatosis than in those with no MASLD (52% vs. 10%; p = 0.03). In the overall cohort, this staining was more intense in patients with metabolic dysfunction-associated steatohepatitis (MASH) than in those without (63% vs. 41%; p = 0.01) and strongly correlated with liver fibrosis and to a lesser extent with liver inflammation. Lanifibranor treatment was associated with more common improvement in CD34 periportal staining (p = 0.025), and less frequent worsening of lobular staining (p = 0.028). Compared with healthy rats, rats with MASLD had higher CD34 staining, portal venous pressure, intrahepatic vascular resistance, and impaired liver endothelial function. Lanifibranor normalised or strongly improved these abnormalities, whereas mono-PPAR agonists caused partial improvements. Conclusions: In patients, LSEC capillarisation was increased at the earliest stages of MASLD and was associated with liver fibrosis and inflammation. In both patients and rats with MASLD, lanifibranor treatment was associated with improvement in liver endothelial phenotype. Impact and implications: Data on changes in liver sinusoidal endothelial cells (LSECs) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and their response to treatment are limited. This study demonstrates that LSEC capillarisation is already present in the lobular zone of the liver of patients and rats at the stage of isolated steatosis, before metabolic dysfunction-associated steatohepatitis (MASH) onset, and progresses with liver fibrosis, and to a lesser extent with liver inflammation. Lanifibranor treatment, a pan-peroxisome proliferator-activated receptor agonist currently tested in a phase III clinical trial, improves LSEC capillarisation but also intrahepatic vascular resistance and portal pressure in MASLD. Targeting LSECs appears to be a promising approach to improve MASH.
