Secreted folate receptor γ drives fibrogenesis in metabolic dysfunction–associated steatohepatitis by amplifying TGFβ signaling in hepatic stellate cells

Abstract

Hepatic fibrosis is the primary determinant of mortality in patients with metabolic dysfunction–associated steatohepatitis (MASH). Transforming growth factor–β (TGFβ), 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 TGFβ antagonism. We have identified that soluble folate receptor γ (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 TGFβ1. We found that FOLR3 interacts with the serine protease HTRA1, a known regulator of TGFBR, and activates TGFβ 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.

Progress in the Study of the Role and Mechanism of HTRA1 in Diseases Related to Vascular Abnormalities

“…HTRA1 plays an important role in vascular homeostasis by regulating signaling pathways or refolding, translocation, and degradation of extracellular matrix proteins, thereby directly or indirectly regulating angiogenesis and vascular remodeling, and vascular and related structural dysfunction caused by abnormal function of the HTRA1 gene is an important initiator and high risk factor. This article suggests that more research on vascular diseases involving cardiovascular, 120 renal, 121 and hepatic diseases 122 should include HTRA1 as an important research target, and even in the process of tissue repair and regeneration, 123 scarring, 124 senescence, 125 , 126 and pregnancy complications 87 should include HTRA1 as an indispensable research component.…”

Role of Folate in Liver Diseases

“…Exogenous FOLR3 stimulates the production of ECM in HSCs, and TGF-β1 synergism further enhances this effect. FOLR3 interacts with the serine protease HTRA1 to activate TGF-β signaling [ 45 ].…”

“…Blocking mitochondrial folate-mediated 1C metabolism promotes the regression of liver fibrosis in NASH mice. Mitochondrial folate metabolism, ALA depletion, and TGF-βR1 production are feed-forward signals that maintain pro-fibrotic TGF-β1 signaling [ 45 ]. Targeting mitochondrial folate to mediate 1C metabolism is a potential strategy to promote the regression of liver fibrosis.…”