MXD3 Promotes Obesity and the Androgen Receptor Signaling Pathway in Gender-Disparity Hepatocarcinogenesis
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 impac...
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MDPI AG
2021-12-01
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| Online Access: | https://www.mdpi.com/2073-4409/10/12/3434 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Yi-Wen Tsai |
| collection | DOAJ |
| description | 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 <i>mxd3</i> 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. |
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| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T04:25:50Z |
| publishDate | 2021-12-01 |
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| series | Cells |
| spelling | doaj.art-7401033f9e9b4c73948170e6851cf8f42023-11-23T07:37:44ZengMDPI AGCells2073-44092021-12-011012343410.3390/cells10123434MXD3 Promotes Obesity and the Androgen Receptor Signaling Pathway in Gender-Disparity HepatocarcinogenesisYi-Wen Tsai0Kuo-Shyang Jeng1Mu-Kuang He2Yang-Wen Hsieh3Hsin-Hung Lai4Chi-Yu Lai5Chun-Chieh Huang6Chiung-Fang Chang7Chung-Tsui Huang8Guor Mour Her9Department of Family Medicine, Chang Gung Memorial Hospital, Keelung 204, TaiwanDivision of General Surgery, Far Eastern Memorial Hospital, New Taipei 220, TaiwanTaipei First Girls High School, Taipei 100, TaiwanDepartment of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung 202, TaiwanInstitute of Biopharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 112, TaiwanInstitute of Biopharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 112, TaiwanDepartment of Radiology, Far Eastern Memorial Hospital, New Taipei 220, TaiwanDivision of General Surgery, Far Eastern Memorial Hospital, New Taipei 220, TaiwanDepartment of Internal Medicine, Division of Gastroenterology and Hepatology, Far Eastern Memorial Hospital, New Taipei 220, TaiwanInstitute of Biopharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 112, TaiwanObesity 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 <i>mxd3</i> 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.https://www.mdpi.com/2073-4409/10/12/3434obesityhepatic steatosissteatohepatitisfibrogenesisliver cancer |
| spellingShingle | 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 MXD3 Promotes Obesity and the Androgen Receptor Signaling Pathway in Gender-Disparity Hepatocarcinogenesis Cells obesity hepatic steatosis steatohepatitis fibrogenesis liver cancer |
| title | MXD3 Promotes Obesity and the Androgen Receptor Signaling Pathway in Gender-Disparity Hepatocarcinogenesis |
| title_full | MXD3 Promotes Obesity and the Androgen Receptor Signaling Pathway in Gender-Disparity Hepatocarcinogenesis |
| title_fullStr | MXD3 Promotes Obesity and the Androgen Receptor Signaling Pathway in Gender-Disparity Hepatocarcinogenesis |
| title_full_unstemmed | MXD3 Promotes Obesity and the Androgen Receptor Signaling Pathway in Gender-Disparity Hepatocarcinogenesis |
| title_short | MXD3 Promotes Obesity and the Androgen Receptor Signaling Pathway in Gender-Disparity Hepatocarcinogenesis |
| title_sort | mxd3 promotes obesity and the androgen receptor signaling pathway in gender disparity hepatocarcinogenesis |
| topic | obesity hepatic steatosis steatohepatitis fibrogenesis liver cancer |
| url | https://www.mdpi.com/2073-4409/10/12/3434 |
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