HKUMed discovers a novel mediator of liver fibrosis and its underlying mechanism that can be a new therapeutic target
A research team from the LKS Faculty of Medicine, The University of Hong Kong (HKUMed) has discovered a new regulator mediating the onset and progression of liver fibrosis. The discovery provides insight into the new mechanism of hepatic fibrogenesis that allows the future development of effective pharmacological therapy for patients with liver fibrosis.
Liver fibrosis is the advanced stage of chronic liver disease that can proceed to cirrhosis and may ultimately result in liver cancer. Although both human and animal studies show that liver fibrosis is potentially reversible, no medication approved by the Food and Drug Administration (FDA) of the United States is available, suggesting the underlying mechanism are still poorly understood. Thus, there is an urgent need for the development of new and effective pharmacological therapies to improve the outcome of liver fibrosis.
The new findings on the pathological role of adipocyte fatty acid binding protein (A-FABP) and its underlying mechanism in liver fibrosis are the concerted efforts of research teams from the Department of Pharmacology and Pharmacy and Department of Medicine, HKUMed and other research institutes including Sun Yat-sen University Cancer Center, Guangdong Pharmaceutical University, the First Affiliated Hospital of Jinan University, and The University of Hong Kong Shenzhen Institute of Research and Innovation (HKU-SIRI). The findings have been published in Advanced Science [link to the publication].
Background
Development of liver fibrosis results in drastic changes in the liver micro-environment, which in turn accelerates disease progression. Capillarisation of liver sinusoidal endothelial cells (LSEC) and activation of hepatic stellate cells (HSC) are the key events in the kickoff and progression of the disease. Upon prolonged damage or stimulation, LSEC undergo capillarisation and exhibit reduced gatekeeper function on HSC activation. Activated HSC secretes extracellular matrix (ECM) molecules leading to ECM accumulation, which could be further enhanced by the stimulation of transforming growth factor-beta 1 (TGFβ1), the key mediator of the fibrogenic cytokine network. Although the pathological function of various hepatic cells in fibrogenesis has been identified, the crosstalk between them remains obscure.
Adipocyte fatty acid-binding protein (A-FABP) is a fat-derived hormone that plays an important role in the uptake, transportation and the metabolism of long-chain fatty acids. It is abundantly expressed in adipocytes while can also be expressed in endothelial cells, macrophages, and dendritic cells. Among liver diseases, A-FABP is closely related to steatohepatitis, cirrhosis, and hepatocellular carcinoma. Clinical studies implicated the involvement of A-FABP in the fibrogenesis of patients with non-alcoholic fatty liver disease (NAFLD), but the exact role and the underlying mechanism have never been investigated.
Research methodology and findings
The research team used A-FABP deficient mice and their wild-type littermates in the study. These mice were subjected to bile duct ligation (BDL) to mimic cholestatic liver fibrosis in human. In the other experiment, wild-type mice subjected to BDL surgery were treated with A-FABP selective inhibitor. The results showed that hepatic A-FABP was significantly increased in wild-type mice after BDL surgery. Liver sinusoidal endothelial cells (LSEC) were identified as the major cellular source of BDL-induced A-FABP.
Genetic deletion and pharmacological inhibition of A-FABP reduced BDL-induced liver fibrosis with suppressed LSEC capillarisation, reduced HSC activation in mice, and attenuated ECM accumulation. The expression of hepatic TGFβ1 was also reduced.
In vitro studies further demonstrated that elevated A-FABP potentiates LSEC capillarisation thus initiates HSC activation. Moreover, LSEC-derived A-FABP stimulated TGFβ1 expression in HSC. Enhanced TGFβ1 perpetuates HSC activation and other fibrogenic events, therefore exaggerating liver fibrosis. The above findings define A-FABP as a novel target for the treatment of liver fibrosis.
Significance
The HKUMed research team is the first to provide evidence that A-FABP is a key regulator of the onset and progression of liver fibrosis by mediating the crosstalk between hepatic cells. This discovery also defines A-FABP as a novel therapeutic target for liver fibrosis. Combining the previous and present findings, the pathogenic role of A-FABP in the whole spectrum of liver disease is further deciphered, which enhances the potential of targeting A-FABP as a therapeutic approach for treating liver diseases.
About the research team
This research was led by Dr Ruby Hoo Lai-chong, Assistant Professor of the Department of Pharmacology and Pharmacy, HKUMed and Co-investigator of State Key Laboratory of Pharmaceutical Biotechnology, HKU. Dr Wu Xiaoping, post-doctoral fellow in the Department of Pharmacology and Pharmacy, HKUMed is the first author. Professor Xu Aimin, Chair Professor of Metabolic Medicine, Department of Medicine, Chair Professor of Department of Pharmacology and Pharmacy, HKUMed, Director of State Key Laboratory of Pharmaceutical Biotechnology, HKU; Professor Karen Lam Siu-ling, Rosie TT Young Professor in Endocrinology and Metabolism, Chair Professor in Medicine, Department of Medicine, HKUMed, Clinical Director of State Key Laboratory of Pharmaceutical Biotechnology, HKU; Dr Shu Lingling, post-doctoral fellow, Department of Medicine, HKUMed and doctor, Sun Yat-sen University Cancer Center; Ms Zhang Zixuan and Ms Zong Jiuyu, postgraduate student; Dr Li Jingjing, post-doctoral fellow, Department of Pharmacology and Pharmacy, HKUMed; Professor Ye Dewei from Guangdong Pharmaceutical University; Dr Song Erfei, post-doctoral fellow and Professor Wang Cunchuan from the First Affiliated Hospital of Jinan University are the co-authors.
Acknowledgements
This study was supported by Health Medical Research Fund (02131906) of the Food and Health Bureau, Government of the Hong Kong Special Administrative Region; Shenzhen Science and Technology Program – Basic Research Program (201605303000678); Collaborative Research Fund (C7037-17W) and Areas of Excellence Scheme (AOE/M-707/18) from Research Grants Council, Government of the Hong Kong Special Administrative Region.