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Journal article
Secreted folate receptor γ drives fibrogenesis in metabolic dysfunction-associated steatohepatitis by amplifying TGFβ signaling in hepatic stellate cells
Science translational medicine, v 15(715), 2966
27 Sep 2023
PMID: 37756380
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Hepatic fibrosis is the primary determinant of mortality in patients with metabolic dysfunction-associated steatohepatitis (MASH). Transforming growth factor-beta (TGF beta), a master profibrogenic cytokine, is a promising therapeutic target that has not yet been translated into an effective therapy in part because of liabilities associated with systemic TGF beta antagonism. We have identified that soluble folate receptor gamma (FOLR3), which is expressed in humans but not in rodents, is a secreted protein that is elevated in the livers of patients with MASH but not in those with metabolic dysfunction-associated steatotic liver disease, those with type II diabetes, or healthy individuals. Global proteomics showed that FOLR3 was the most highly significant MASH-specific protein and was positively correlated with increasing fibrosis stage, consistent with stimulation of activated hepatic stellate cells (HSCs), which are the key fibrogenic cells in the liver. Exposure of HSCs to exogenous FOLR3 led to elevated extracellular matrix (ECM) protein production, an effect synergistically potentiated by TGF beta 1. We found that FOLR3 interacts with the serine protease HTRA1, a known regulator of TGFBR, and activates TGF beta signaling. Administration of human FOLR3 to mice induced severe bridging fibrosis and an ECM pattern resembling human MASH. Our study thus uncovers a role of FOLR3 in enhancing fibrosis.
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Details
- Title
- Secreted folate receptor γ drives fibrogenesis in metabolic dysfunction-associated steatohepatitis by amplifying TGFβ signaling in hepatic stellate cells
- Creators
- Connor Quinn - Temple UniversityMario C. Rico - Temple UniversityCarmen Merali - Temple UniversityCarlos A. Barrero - Temple UniversityOscar Perez-Leal - Temple UniversityVictoria Mischley - Drexel University, Biochemistry and Molecular BiologyJohn Karanicolas - Temple Univ, Sch Pharm, Philadelphia, PA 19140 USAScott L. Friedman - Icahn Sch Med Mt Sinai, Div Liver Dis, New York, NY 10029 USASalim Merali - Temple University
- Publication Details
- Science translational medicine, v 15(715), 2966
- Publisher
- American Association for the Advancement Science
- Number of pages
- 14
- Grant note
- YFAC142023; 5R01DK128289-03 / Flight Attendant Medical Research Institute (FAMRI) Young Clinical Scientist Award YFAC142023; R43AR081768-01; NIH-R43AR081768-01; R21HG012241; NIH-R21HG012241 / Temple University through discretionary funds allocated 5R01DK128289-03 / Fox Chase core grant Fox Chase core YFAC142023; R43AR081768-01; NIH-R43AR081768-01; R21HG012241; NIH-R21HG012241 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Flight Attendant Medical Research Institute (FAMRI) through Young Clinical Scientist Award
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Drexel University
- Web of Science ID
- WOS:001082818900005
- Scopus ID
- 2-s2.0-85172806348
- Other Identifier
- 991021861215504721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Cell Biology
- Medicine, Research & Experimental