Mxd3 promotes obesity and the androgen receptor signaling pathway in gender‐disparity hepatocarcinogenesis

Yi Wen Tsai, Kuo Shyang Jeng, Mu Kuang He, Yang Wen Hsieh, Hsin Hung Lai, Chi Yu Lai, Chun Chieh Huang, Chiung Fang Chang, Chung Tsui Huang, Guor Mour Her*

*此作品的通信作者

研究成果: Article同行評審

1 引文 斯高帕斯(Scopus)

摘要

Obesity is closely linked to metabolic diseases, particularly non‐alcoholic steatohepatitis (NASH) or non‐alcoholic fatty liver disease (NAFLD), ultimately leading to hepatocellular carcinoma (HCC). However, the molecular mechanisms of NASH‐associated HCC (NAHCC) remain elusive. To explore the impact of Max dimerization protein 3 (MXD3), a transcription factor that regulates several cellular functions in disorders associated with metabolic diseases, we conditionally expressed Mxd3 proteins using Tet‐on mxd3 transgenic zebrafish (MXs) with doxycycline (MXs + Dox) or without doxycycline (MXs − Dox) treatment. Overexpression of global MXD3 (gMX) or hepatic Mxd3 (hMX) was associated with obesity‐related NAFLD pathophysiology in gMX + Dox, and liver fibrosis and HCC in hMX + Dox. Oil Red O (ORO)‐stained signals were seen in intravascular blood vessels and liver buds of larval gMX + Dox, indicating that Mxd3 functionally promotes lipogenesis. The gMX + Dox‐treated young adults exhibited an increase in body weight and visceral fat accumulation. The hMX + Dox‐treated young adults showed normal body characteristics but exhibited liver steatosis and NASH‐like phenotypes. Subsequently, steatohepatitis, liver fibrosis, and NAHCC were found in 6‐month‐old gMX + Dox adults compared with gMX − Dox adults at the same stage. Overexpression of Mxd3 also enhanced AR expression accompanied by the increase of AR‐signaling pathways resulting in hepatocarcinogenesis in males. Our results demonstrate that global actions of Mxd3 are central to the initiation of obesity in the gMX zebrafish through their effects on adipogenesis and that MXD3 could serve as a therapeutic target for obesity‐associated liver diseases.

原文English
文章編號3434
期刊Cells
10
發行號12
DOIs
出版狀態Published - 12月 2021

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