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.

Highlights

  • Liver fibrosis is a major cause of mortality worldwide [1]

  • Quantification of densitometry determined that TSP-1 expression was significantly increased (242.6%, p = 0.02) after primary human hepatic stellate cells (HSCs) were treated for 48 hours with 1 μg/ml TGF-β1 compared to vehicle treated HSCs

  • A key difference to note between our study and Soto-Pantoja et al is that their study examined impact of high fat diet on TSP-1 deficiency in Apc min/+ mice, whereas our study examined the impact of choline deficient, limited methionine and high fat diet driven model of hepatic fibrosis with TSP-1 deficiency in C57BL/6J background

Read more

Summary

Introduction

Liver fibrosis is a major cause of mortality worldwide [1]. It could be a pathological manifestation of various disorders such as metabolic imbalance, viral or parasitic infection and exposure to toxins such as excess alcohol [2]. A prolonged state of inflammation and fibrosis without proper injury resolution in the liver may lead to cirrhosis, hepatic carcinoma and death. NAFLD-related liver cirrhosis is projected to be the leading cause of liver transplantation in the United States by 2020 [6]. Diagnosis of NAFLD is often made after significant advancement of diseases such as development of steatohepatitis, fibrosis, and cirrhosis and/or hepatocellular carcinoma. A better understanding of the mechanism behind progression of NAFLD is needed to develop successful therapies for NAFLD

Methods
Results
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call