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

• 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
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2012.10.022

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.