Thrombospondin-2 is a novel biomarker for advanced fibrosis and potential therapeutic target in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is becoming a major cause of end-stage liver disease and the severity of liver fibrosis is associated with adverse hepatic outcomes. We conducted omics analysis to search for its noninvasive diagnostic biomarker and potential therapeutic target. We performed RNA-sequencing of liver tissues from 98 histologically characterized NAFLD patients. Transcriptome analysis identified the expression of thrombospondin-2 (THBS2) significantly upregulated in advanced fibrosis (F3-4) patients. Intrahepatic THBS2 mRNA levels showed the highest areas under the receiver operating characteristic curve (AUROC) of 0.957 for diagnosing advanced fibrosis and strongly correlated with COL1A1 and COL1A2 mRNA levels (r = 0.899 and 0.912, respectively). Serum levels of TSP-2, a secreted protein encoded by THBS2, were measured in another cohort of 213 histologically characterized NAFLD patients and significantly elevated in advanced fibrosis patients. AUROC for diagnosing advanced fibrosis was 0.858. Serum TSP-2 was an independent predictor of advanced fibrosis in multivariate analysis and stratified NAFLD patients according to the risk of adverse hepatic outcomes. THBS2 was mainly expressed in hepatic stellate cells (HSCs) in the liver and knockdown of THBS2 significantly suppressed the expressions of type I collagen genes (COL1A1 and COL1A2) in a HSC line LX-2. In conclusion, thrombospondin-2 may be a novel diagnostic biomarker for advanced fibrosis and a potential therapeutic target in NAFLD patients.