Amlexanox reversed non-alcoholic fatty liver disease through IKKε inhibition of hepatic stellate cell

• Published in: Life sciences (1973) Vol. 239; p. 117010
• Main Authors: He, Qian, Xia, Xuan, Yao, Kecheng, Zeng, Jun, Wang, Wei, Wu, Qiong, Tang, Renmin, Zou, Xiulan
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 15.12.2019; Elsevier BV
• Subjects: Actin; Actins - antagonists & inhibitors; AKT protein; Aminopyridines - pharmacology; Aminopyridines - therapeutic use; Amlexanox; Animal models; Animals; Biochemistry; Body Weight - drug effects; Diabetes mellitus; Energy Metabolism - drug effects; Enzyme-linked immunosorbent assay; Fatty liver; Gene Expression - drug effects; Glucose; Glucose - metabolism; Hepatic stellate cell; Hepatic Stellate Cells - drug effects; Hepatic Stellate Cells - metabolism; Hepatic Stellate Cells - pathology; Hepatocytes; Hepatocytes - drug effects; Hepatocytes - pathology; High fat diet; I-kappa B Kinase - antagonists & inhibitors; IKKε; Immunohistochemistry; Inflammation; Insulin; Insulin receptor substrate 1; Kinases; Lipid metabolism; Lipid Metabolism - drug effects; Lipid Metabolism - genetics; Lipids; Lipopolysaccharides; Liver; Liver diseases; Male; Mice; Mice, Inbred C57BL; Molecular modelling; Muscles; NAFLD; NF-κB protein; Non-alcoholic Fatty Liver Disease - drug therapy; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - pathology; Oils & fats; Polymerase chain reaction; Signal transduction; Signal Transduction - drug effects; Signaling; Smooth muscle; Staining; Steatosis; Stellate cells; Western blotting; NAFLD; Amlexanox; Hepatic stellate cell; IKKε
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2019.117010

Amlexanox, an inhibitor of nuclear factor κB kinase epsilon (IKKε) and TANK-binding kinase 1(TBK1), was demonstrated to be effective in diabetes and obesity. The aim of this study was to explore the molecular mechanisms of its role in non-alcoholic fatty liver disease (NAFLD). NAFLD mouse models were established by using eight-week-old male C57BL/6 mice fed with high-fat diet (HFD) or (and) lipopolysaccharide (LPS) for 18 weeks. From the beginning of HFD, HFD-induced mice were subjected to amlexanox or vehicle for 18 weeks. HFD + LPS-induced mice were treated with amlexanox or vehicle for the last 6 weeks. Blood biochemistry parameters were determined using automatic biochemistry analyzer. Histological changes of liver tissue were observed by hematoxylin-eosin (H&E) staining and Oil Red O staining. The expressions of IKKε and smooth muscle actin-α (α-SMA) were evaluated through immunohistochemistry. Serum inflammatory mediator was determined by enzyme linked immunosorbent assay (ELISA). Gene expressions involved in glucose and lipid metabolism, insulin signaling pathway were examined using quantitative RT-PCR or Western blotting. This study demonstrated that amlexanox reversed glucose and lipid metabolic disturbance and hepatic steatosis in NAFLD mice model. IKKε was specific expressed in hepatic stellate cells (HSCs) instead of hepatocytes. This study also found that amlexanox improved insulin signaling (Insulin-IRS-1-Akt) in hepatocytes through inhibiting inflammation (IKKε-NF-κB-TNF-α/IL-1α) in HSCs. The present study confirmed that IKKε was specific expressed in HSCs. Inhibition of activated HSCs was responsible for effects of amlexanox on NAFLD, with improving insulin signal pathway in hepatocytes.