Scandinavian journal of gastroenterology · 2026
Fibroblast activation protein and down-stream effects on its substrates in metabolic dysfunction-associated steatotic liver disease.
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Hansson Sara F, Nasr Patrik, Knöchel Jane, Miliotis Tasso, Andréasson Anne-Christine, Hober Andreas, Nyström Ann-Christin, Bergenholm Linnéa, Karimi Mahssa, Peng Xiao-Rong, Ekstedt Mattias, Kechagias Stergios, Liljeblad Mathias
Аннотация
BACKGROUND: Fibroblast activation protein (FAP) is a serine protease upregulated in liver and blood in patients with chronic liver disease of several etiologies. FAP has a pro-fibrotic effect and may also regulate disease progression by proteolytically affecting two circulating substrates, fibroblast growth factor 21 (FGF21) and α2-antiplasmin (α2AP). The aim of this study was to investigate the involvement of FAP in metabolic dysfunction-associated steatotic liver disease (MASLD).
METHODS: FAP protein levels were measured in liver biopsies (n = 47) and plasma samples (n = 79) from an extensively characterized longitudinal MASLD cohort. FAP-cleaved and -uncleaved forms of α2AP were measured with a novel mass spectrometry-based method, using isotopically labeled recombinant protein fragments as internal standards. Total and intact FGF21 levels were quantified using ELISA. Results were correlated to histopathological steatosis grade, inflammation grade, ballooning grade and fibrosis stage.
RESULTS: Both liver and plasma levels of FAP were increased in patients with advanced fibrosis, stage 3-4 vs 0-2 (p < 0.005) but were not affected by steatosis grade. The fraction of FAP-cleaved α2AP correlated with the plasma FAP level and was significantly higher in patients with fibrosis stage 3-4 (p < 0.05). In contrast, plasma FAP did not correlate with the ratio of intact FGF21.
CONCLUSION: These results show that FAP expression is increased in more advanced hepatic fibrosis. This suggests that FAP might be involved in the pathophysiology of MASLD progression and could be a biomarker for advanced hepatic fibrosis. Studies in larger prospective cohorts are needed to confirm these findings.
METHODS: FAP protein levels were measured in liver biopsies (n = 47) and plasma samples (n = 79) from an extensively characterized longitudinal MASLD cohort. FAP-cleaved and -uncleaved forms of α2AP were measured with a novel mass spectrometry-based method, using isotopically labeled recombinant protein fragments as internal standards. Total and intact FGF21 levels were quantified using ELISA. Results were correlated to histopathological steatosis grade, inflammation grade, ballooning grade and fibrosis stage.
RESULTS: Both liver and plasma levels of FAP were increased in patients with advanced fibrosis, stage 3-4 vs 0-2 (p < 0.005) but were not affected by steatosis grade. The fraction of FAP-cleaved α2AP correlated with the plasma FAP level and was significantly higher in patients with fibrosis stage 3-4 (p < 0.05). In contrast, plasma FAP did not correlate with the ratio of intact FGF21.
CONCLUSION: These results show that FAP expression is increased in more advanced hepatic fibrosis. This suggests that FAP might be involved in the pathophysiology of MASLD progression and could be a biomarker for advanced hepatic fibrosis. Studies in larger prospective cohorts are needed to confirm these findings.