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Amlexanox Reversed Non-Alcoholic Fatty Liver Disease Through IKKε Inhibition of Hepatic Stellate Cell

Amlexanox Reversed Non-Alcoholic Fatty Liver Disease Through IKKε Inhibition of Hepatic Stellate Cell

Qian He, Xuan Xia, Kecheng Yao, Jun Zeng, Wei Wang, Qiong Wu, Renmin Tang, Xiulan Zou

Life Sci. 2019 Dec 15;239:117010.

PMID: 31672578

Abstract:

Aims:
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).
Main methods:
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.
Key findings:
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.
Significance:
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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP68302578	Amlexanox		68302-57-8	Price

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