Thrombospondin-2 as a potential diagnostic biomarker and therapeutic target of nonalcoholic fatty liver disease

Professor Xu, Aimin   (Principal Investigator (PI))

Dr Liu Yan   (Co-Investigator)

42

2022-01-01

1496160

Thrombospondin-2 as a potential diagnostic biomarker and therapeutic target of nonalcoholic fatty liver disease

Antibody Therapeutics, Biomarker, Hepatokines, Metabolic liver disease, metabolic syndrome, Nonalcoholic steatohepatitis

Others - Medicine, Dentistry and Health

08192316

Health and Medical Research Fund - Full Grant

2020

On-going

Background: Nonalcoholic fatty liver disease (NAFLD) comprises a spectrum of liver disorders from simple steatosis to steatohepatitis (NASH), fibrosis, cirrhosis, and liver cancer. NALFD is the most common chronic liver disease worldwide and is closely associated with overweight/obesity. There is currently no approved drug available for treatment of NAFLD. The lack of non-invasive, cost-effective diagnostic tool for NAFLD stratification and risk prediction represent another major challenge for management of NAFLD/NASH. Preliminary data: We have identified circulating thrombonspondin-2, a secreted glycoprotein, is progressively increased in obese Chinese from normal liver, simple steatosis, borderline NASH and NASH, and is closely associated with histological scores of steatosis and fibrosis and markers of NASH. Furthermore, recombinant thrombonspondin-2 stimulates the production of pro-inflammatory cytokines and pro-fibrogenic factors in Kupffer cells and hepatic stellate cells (HSCs) respectively. Hypothesis: Thrombonspondin-2 is a potential diagnostic biomarker for stratifying the severity of NAFLD. Elevated hepatic expression of thrombonspondin-2 contributes to the pathogenesis of NAFLD/NASH through its actions in Kupffer cells and HSCs. Neutralization of thrombonspondin-2 represents a promising therapeutic strategy for NAFLD. Aims:(1) To investigate whether hepatic expression of thrombonspondin-2 mirrors the changes of its circulating level during the progression of NAFLD in liver biopsies of obese Chinese receiving bariatric surgery; (2) To evaluate whether knockdown of hepatic thrombonspondin-2 expression or antibody-mediated neutralization of thrombonspondin-2 alleviates diet-induced NAFLD/NASH in mice. Outcomes: These findings will provide potential diagnostic tool to stratify the severity of NAFLD, and a new therapeutic target for future development of anti-NAFLD drugs.