Pharmacological inhibition of adipocyte fatty acid binding protein alleviates both acute liver injury and non-alcoholic steatohepatitis in mice

Background & Aims Adipocyte fatty acid binding protein (A-FABP) is a key mediator of inflammatory response in macrophages. Increased hepatic expression and circulating levels of A-FABP have been observed in patients with non-alcoholic fatty liver disease (NAFLD). Here, we investigated the role o...

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Bibliographic Details
Published in:Journal of hepatology 2013-02, Vol.58 (2), p.358-364
Main Authors: Hoo, Ruby L.C, Lee, Ida P.C, Zhou, Mi, Wong, Janice Y.L, Hui, Xiaoyan, Xu, Aimin, Lam, Karen S.L
Format: Article
Language:English
Subjects:
Acute Lung Injury - chemically induced
Acute Lung Injury - metabolism
Acute Lung Injury - prevention & control
Adenoviridae - genetics
Animals
Biological and medical sciences
Biphenyl Compounds - pharmacology
Cholesterol, Dietary - adverse effects
Cytokines - metabolism
Dietary Fats - adverse effects
Disease Models, Animal
Fatty Acid-Binding Proteins - antagonists & inhibitors
Fatty Acid-Binding Proteins - drug effects
Fatty Acid-Binding Proteins - genetics
Fatty Acid-Binding Proteins - metabolism
Fatty Acid-Binding Proteins - physiology
Fatty Liver - chemically induced
Fatty Liver - metabolism
Fatty Liver - prevention & control
Gastroenterology and Hepatology
Gastroenterology. Liver. Pancreas. Abdomen
Inflammation
Kupffer cells
Kupffer Cells - drug effects
Kupffer Cells - metabolism
Kupffer Cells - pathology
Lipopolysaccharides - adverse effects
Liver - drug effects
Liver - metabolism
Liver - pathology
Liver. Biliary tract. Portal circulation. Exocrine pancreas
Macrophages - drug effects
Macrophages - metabolism
Macrophages - pathology
Male
Medical sciences
Metabolic diseases
Mice
Mice, Inbred C57BL
Mice, Mutant Strains
NF-kappa B - metabolism
Non-alcoholic Fatty Liver Disease
Non-alcoholic steatohepatitis
Obesity
Other diseases. Semiology
Proto-Oncogene Proteins c-jun - metabolism
Pyrazoles - pharmacology
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Summary:Background & Aims Adipocyte fatty acid binding protein (A-FABP) is a key mediator of inflammatory response in macrophages. Increased hepatic expression and circulating levels of A-FABP have been observed in patients with non-alcoholic fatty liver disease (NAFLD). Here, we investigated the role of A-FABP in both lipopolysaccaride (LPS)-induced acute liver injury and high fat high cholesterol (HFHC) diet-induced NAFLD in mice. Methods Mice with LPS-induced acute liver injury and HFHC diet-induced obesity were treated with the A-FABP inhibitor BMS309403. Liver tissues of the mice were analyzed by immunohistochemistry, Western blot or real-time PCR. Results A-FABP expression in Kupffer cells was significantly elevated in mice with LPS-induced acute liver injury and HFHC diet-induced obesity, as compared to their healthy controls. Pretreatment of mice with BMS309403 led to a diminished LPS-induced elevation in serum levels of alanine transaminase and hepatic production of pro-inflammatory cytokines. Likewise, chronic treatment of HFHC diet-induced obese mice with BMS309403 ameliorated hepatic steatosis, macrophage infiltration, and cellular ballooning of hepatocytes. Such improvements in liver function and morphology were accompanied by significantly decreased activation of both c-Jun and NF-κB. Pretreatment with BMS309403 suppressed both LPS- and palmitate-induced pro-inflammatory responses in isolated rat Kupffer cells. Adenovirus-mediated ectopic expression of A-FABP alone was sufficient to induce liver injury and inflammation in mice. Conclusions These findings suggest that A-FABP is an important contributor to both LPS-induced acute liver injury and diet-induced NAFLD by potentiating inflammation in Kupffer cells. Pharmacological inhibition of A-FABP may represent a promising modality for obesity-related non-alcoholic steatohepatitis.
ISSN:0168-8278
1600-0641
DOI:10.1016/j.jhep.2012.10.022