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

Abstract

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.

Serum thrombospondin 2 is a novel predictor for the severity in the patients with NAFLD

“…Recently, elevated hepatic expression of another thrombospondin family, TSP1 , has been reported in NAFLD patients and mice 21,22 . However, serum TSP1 data from human serum are limited, 23 and no studies have widely examined the correlations between serum TSP1 levels and NAFLD histopathology, including ballooning grade and fibrosis stage.…”

Macrophage-derived thrombospondin 1 promotes obesity-associated non-alcoholic fatty liver disease

“…Discussion TSP1 is a multifunctional secreted matricellular protein and has been involved in the pathogenesis of many diseases such as cardiovascular disease, renal complications, obesity and insulin resistance. However, the role of TSP1 in the non-alcoholic fatty liver disease (NAFLD)/ non-alcoholic steatohepatitits (NASH) is largely unknown 16,17 . In this study, by utilization of tissue specific TSP1 knockout mice, we demonstrate that macrophage-specific TSP1 deletion but not adipocyte-specific TSP1 deletion protects mice against obesity-associated liver injury, accompanied by reduced liver inflammation and fibrosis.…”

“…In addition to regulating liver macrophage pro-inflammatory status as discussed above, through paracrine effects, macrophage-derived TSP1 may directly modulate the function of other liver cells such as hepatocyte, stellate cells or sinusoidal endothelial cells and impact the development and progression of NAFLD/NASH 17,47,48 . It has been shown that TSP1 inhibition or knockdown in cultured stellate cell attenuated TGF-β -induced stellate cell activation (e.g.…”

“…It has been shown that TSP1 inhibition or knockdown in cultured stellate cell attenuated TGF-β -induced stellate cell activation (e.g. production of smooth muscle alpha actin and collagen) 17 . In addition, PDGF-induced TSP1 J o u r n a l P r e -p r o o f expression in hepatic stellate cells is prerequisite for TGF-β's effect on stellate cell activation 48 .…”

“…Previously, studies from our lab and others demonstrate that TSP1 plays a role in cardiovascular and renal diseases 13,14 . TSP1 is also involved in tissue injury, inflammatory diseases, and NAFLD [15][16][17] . Recent studies from our lab have demonstrated a novel role for TSP1 in both recruitment and pro-inflammatory activation of macrophages 18 .…”