Merali, S. | Search bioRxiv

bioRxiv2022

Secreted folate receptor-gamma drives fibrogenesis in nonalcoholic steatohepatitis by amplifying TGFβ signaling in hepatic stellate cells

Hepatic fibrosis is the primary determinant of mortality in nonalcoholic steatohepatitis (NASH) patients. Antagonism of 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, due in part to the lack of animal models resembling the human phenotype of NASH. Here we have identified that soluble secreted folate receptor gamma (FOLR3), expressed in humans but not rodents, is a secreted protein that is elevated in livers of NASH subjects but not in subjects with nonalcoholic fatty liver, type II diabetes, or healthy subjects. FOLR3, based on global proteomics, was the most highly expressed NASH-specific protein and positively correlated with increasing fibrosis stages, suggesting an impact on activated hepatic stellate cells (HSCs), the key fibrogenic cell in the liver. Exposure of stellate cells to exogenous FOLR3 led to elevated extracellular matrix (ECM) protein production, an effect synergistic with TGF{beta}1. Structurally, FOLR3 interacts with serine protease HTRA1, which downregulates TGF{beta} signaling through the degradation of its receptor TGFBR2. Administration of human FOLR3 to mice induced severe bridging fibrosis and an ECM pattern resembling human NASH. Our study uncovers a novel role of FOLR3 in enhancing fibrosis and identifies FOLR3 as a potential therapeutic target in NASH fibrosis. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/500829v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@1ac3ce3org.highwire.dtl.DTLVardef@d1945corg.highwire.dtl.DTLVardef@1632eb1org.highwire.dtl.DTLVardef@8e8d21_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2021

Role of glycine-N-methyl transferase in human and murine nonalcoholic steatohepatitis

Non-alcoholic fatty liver disease (NAFLD) has become one of the most prominent forms of chronic liver disease worldwide, mirroring the obesity epidemic. NAFLD is the number one cause of chronic liver disease worldwide, with 25% of these patients developing nonalcoholic steatohepatitis (NASH). This significantly increases the risk of cirrhosis and decompensated liver failure. Past studies in rodent models have shown that the knockout of glycine-N-methyltransferase (GNMT) is associated with steatosis, fibrosis, and hepatocellular carcinoma. However, the attenuation of GNMT in subjects with NASH and the molecular basis for its impact on the disease process have yet to be elucidated. To address this knowledge gap, we show the reduction of GNMT protein levels in the liver of NASH subjects compared to healthy controls. To gain insight into the impact of decreased GNMT in the disease process, we performed global label-free proteome studies on the livers from a murine Western diet-based model of NASH. We identified the differential expression of essential proteins involved in hallmark NASH pathogenesis, including lipid metabolism, inflammation, and fibrosis. Significantly, the downregulation of GNMT, the prominent regulator of S-adenosylmethionine (AdoMet), was identified as a contributing factor to these networks, increasing fourfold in AdoMet levels. AdoMet is an essential metabolite for transmethylation reactions and a substrate for polyamine synthesis, and its levels can impact polyamine flux and generate oxidative stress. Therefore, we performed targeted proteome and metabolomics studies to show a decrease in GNMT transmethylation, an increase in flux through the polyamine pathway, and increased oxidative stress. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=87 SRC="FIGDIR/small/470998v1_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@86cc7borg.highwire.dtl.DTLVardef@1dab0f2org.highwire.dtl.DTLVardef@97009eorg.highwire.dtl.DTLVardef@1a99cf7_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗