Thrombospondin-I is a critical modulator in non-alcoholic steatohepatitis (NASH).

Autor: Min-DeBartolo J; BioMedicine Design, Pfizer Worldwide Research and Development, Cambridge, Massachusetts, United States of America.; Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts, United States of America., Schlerman F; Inflammation and Immunology Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts, United States of America., Akare S; Drug Safety Research and Development, Pfizer Worldwide Research and Development, Groton, Connecticut, United States of America., Wang J; Inflammation and Immunology Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts, United States of America., McMahon J; Inflammation and Immunology Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts, United States of America., Zhan Y; Drug Safety Research and Development, Pfizer Worldwide Research and Development, Groton, Connecticut, United States of America., Syed J; Drug Safety Research and Development, Pfizer Worldwide Research and Development, Groton, Connecticut, United States of America., He W; Early Clinical Development, Pfizer Worldwide Research and Development, Cambridge, Massachusetts, United States of America., Zhang B; Early Clinical Development, Pfizer Worldwide Research and Development, Cambridge, Massachusetts, United States of America., Martinez RV; Inflammation and Immunology Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts, United States of America.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2019 Dec 31; Vol. 14 (12), pp. e0226854. Date of Electronic Publication: 2019 Dec 31 (Print Publication: 2019).
DOI: 10.1371/journal.pone.0226854
Abstrakt: Non-alcoholic fatty liver disease (NAFLD) is a progressive liver disease characterized by dysregulated lipid metabolism and chronic inflammation ultimately resulting in fibrosis. Untreated, NAFLD may progress to non-alcoholic steatohepatitis (NASH), cirrhosis and death. However, currently there are no FDA approved therapies that treat NAFLD/NASH. Thrombospondin-I (TSP-1) is a large glycoprotein in the extracellular matrix that regulates numerous cellular pathways including transforming growth factor beta 1 (TGF-β1) activation, angiogenesis, inflammation and cellular adhesion. Increased expression of TSP-1 has been reported in various liver diseases; however, its role in NAFLD/NASH is not well understood. We first examined TSP-1 modulation in hepatic stellate cell activation, a critical initiating step in hepatic fibrosis. Knockdown or inhibition of TSP-1 attenuated HSC activation measured by alpha smooth muscle actin (α-SMA) and Collagen I expression. To investigate the impact of TSP-1 modulation in context of NAFLD/NASH, we examined the effect of TSP-1 deficiency in the choline deficient L-amino acid defined high fat diet (CDAHFD) model of NASH in mice by assessing total body and liver weight, serum liver enzyme levels, serum lipid levels, liver steatosis, liver fibrosis and liver gene expression in wild type (WT) and TSP-1 null mice. CDAHFD fed mice, regardless of genotype, developed phenotypes of NASH, including significant increase in liver weight and liver enzymes, steatosis and fibrosis. However, in comparison to WT, CDAHFD-fed TSP-1 deficient mice were protected against numerous NASH phenotypes. TSP-1 null mice exhibited a decrease in serum lipid levels, inflammation markers and hepatic fibrosis. RNA-seq based transcriptomic profiles from the liver of CDAHFD fed mice determined that both WT and TSP-1 null mice exhibited similar gene expression signatures following CDAHFD, similar to biophysical and histological assessment comparison. Comparison of transcriptomic profiles based on genotype suggested that peroxisome proliferator activated receptor alpha (PPARα) pathway and amino acid metabolism pathways are differentially expressed in TSP-1 null mice. Activation of PPARα pathway was supported by observed decrease in serum lipid levels. Our findings provide important insights into the role of TSP-1 in context of NAFLD/NASH and TSP-1 may be a target of interest to develop anti-fibrotic therapeutics for NAFLD/NASH.
Competing Interests: The authors have commercial affiliations to Pfizer Worldwide Research and Development, Biogen and Wave Life Sciences and these affiliations do not alter our adherence to PLOS ONE policies on sharing data and materials.
Databáze: MEDLINE
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