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postgraduate thesis: Impact of adipocyte fatty acid binding protein on the pathogenesis of cholestatic liver fibrosis
Title | Impact of adipocyte fatty acid binding protein on the pathogenesis of cholestatic liver fibrosis |
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Authors | |
Advisors | |
Issue Date | 2019 |
Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
Citation | Wu, X. [吴晓萍]. (2019). Impact of adipocyte fatty acid binding protein on the pathogenesis of cholestatic liver fibrosis. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. |
Abstract | During the development of chronic liver disease, fibrosis is a potential reversible stage before liver cirrhosis and hepatocellular carcinoma (HCC). Liver fibrosis is characterized with the activation of hepatic stellate cells (HSCs), which contributes to the excessive accumulation of extracellular matrix proteins (ECM). In the microenvironment of liver, crosstalk mediated by cytokines between different hepatic cells contributes to the development of liver fibrosis. Within the network of fibrogenic cytokine regulation, transforming growth factor-beta (TGFβ) is regarded as the central regulator that potentiates the hepatic fibrogenesis. On the other hand, adipocyte fatty acid binding protein (A-FABP) is an adipokine that closely associates with the different stages of liver injury, such as non-alcoholic fatty liver disease (NAFLD), liver cirrhosis, and HCC. The current study is aimed at investigating whether A-FABP plays a role in the development of liver fibrosis as well as its underlying mechanism. To this end, eight-week-old A-FABP knockout (KO) mice and their WT littermates were subjected to experimental models of liver fibrosis, such as two-week bile duct ligation (BDL) and eight-week carbon tetrachloride (CCl4) exposure. The A-FABP expression, liver injury, and hepatic cytokine regulation were then accessed. Furthermore, both ex vivo and in vitro studies were used to investigate the underlying mechanism.
Key findings
1. Both circulating and hepatic level of A-FABP was significantly increased in mice subjected to BDL or CCl4 exposure. Specifically, sinusoidal endothelial cells

(SECs) were identified as the primary hepatocellular source of A-FABP.
2. A-FABP deficiency protected against either BDL- or CCl4-induced liver fibrosis in mice as indicated by attenuated the liver necrosis, HSC activation, and ECM
accumulation.
3. A-FABP deficiency attenuates the induction of hepatic TGFβ1 upon BDL or
chronic CCl4 exposure.
4. SECs-derived A-FABP stimulated the expression of TGFβ1 in HSCs by activating
the JNK/AP-1 pathway.
5. Pharmacological inhibition of A-FABP by BMS309403 attenuated the
development of BDL-induced liver fibrosis.
These findings suggest A-FABP is a key mediator of the crosstalk between SECs and HSCs cell contributing to the pathogenesis of liver fibrosis. Pharmacological inhibition of A-FABP may represent a novel therapeutic approach for treating liver fibrosis. |
Degree | Doctor of Philosophy |
Subject | Fatty acid-binding proteins Liver - Fibrosis - Pathogenesis |
Dept/Program | Pharmacology and Pharmacy |
Persistent Identifier | http://hdl.handle.net/10722/301051 |
DC Field | Value | Language |
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dc.contributor.advisor | Hoo, RLC | - |
dc.contributor.advisor | Xu, A | - |
dc.contributor.author | Wu, Xiaoping | - |
dc.contributor.author | 吴晓萍 | - |
dc.date.accessioned | 2021-07-16T14:38:43Z | - |
dc.date.available | 2021-07-16T14:38:43Z | - |
dc.date.issued | 2019 | - |
dc.identifier.citation | Wu, X. [吴晓萍]. (2019). Impact of adipocyte fatty acid binding protein on the pathogenesis of cholestatic liver fibrosis. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. | - |
dc.identifier.uri | http://hdl.handle.net/10722/301051 | - |
dc.description.abstract | During the development of chronic liver disease, fibrosis is a potential reversible stage before liver cirrhosis and hepatocellular carcinoma (HCC). Liver fibrosis is characterized with the activation of hepatic stellate cells (HSCs), which contributes to the excessive accumulation of extracellular matrix proteins (ECM). In the microenvironment of liver, crosstalk mediated by cytokines between different hepatic cells contributes to the development of liver fibrosis. Within the network of fibrogenic cytokine regulation, transforming growth factor-beta (TGFβ) is regarded as the central regulator that potentiates the hepatic fibrogenesis. On the other hand, adipocyte fatty acid binding protein (A-FABP) is an adipokine that closely associates with the different stages of liver injury, such as non-alcoholic fatty liver disease (NAFLD), liver cirrhosis, and HCC. The current study is aimed at investigating whether A-FABP plays a role in the development of liver fibrosis as well as its underlying mechanism. To this end, eight-week-old A-FABP knockout (KO) mice and their WT littermates were subjected to experimental models of liver fibrosis, such as two-week bile duct ligation (BDL) and eight-week carbon tetrachloride (CCl4) exposure. The A-FABP expression, liver injury, and hepatic cytokine regulation were then accessed. Furthermore, both ex vivo and in vitro studies were used to investigate the underlying mechanism. Key findings 1. Both circulating and hepatic level of A-FABP was significantly increased in mice subjected to BDL or CCl4 exposure. Specifically, sinusoidal endothelial cells  (SECs) were identified as the primary hepatocellular source of A-FABP. 2. A-FABP deficiency protected against either BDL- or CCl4-induced liver fibrosis in mice as indicated by attenuated the liver necrosis, HSC activation, and ECM accumulation. 3. A-FABP deficiency attenuates the induction of hepatic TGFβ1 upon BDL or chronic CCl4 exposure. 4. SECs-derived A-FABP stimulated the expression of TGFβ1 in HSCs by activating the JNK/AP-1 pathway. 5. Pharmacological inhibition of A-FABP by BMS309403 attenuated the development of BDL-induced liver fibrosis. These findings suggest A-FABP is a key mediator of the crosstalk between SECs and HSCs cell contributing to the pathogenesis of liver fibrosis. Pharmacological inhibition of A-FABP may represent a novel therapeutic approach for treating liver fibrosis. | - |
dc.language | eng | - |
dc.publisher | The University of Hong Kong (Pokfulam, Hong Kong) | - |
dc.relation.ispartof | HKU Theses Online (HKUTO) | - |
dc.rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works. | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.subject.lcsh | Fatty acid-binding proteins | - |
dc.subject.lcsh | Liver - Fibrosis - Pathogenesis | - |
dc.title | Impact of adipocyte fatty acid binding protein on the pathogenesis of cholestatic liver fibrosis | - |
dc.type | PG_Thesis | - |
dc.description.thesisname | Doctor of Philosophy | - |
dc.description.thesislevel | Doctoral | - |
dc.description.thesisdiscipline | Pharmacology and Pharmacy | - |
dc.description.nature | published_or_final_version | - |
dc.date.hkucongregation | 2019 | - |
dc.identifier.mmsid | 991044390192303414 | - |