Small heterodimer partner overexpression partially protects against liver tumor development in farnesoid X receptor knockout mice
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- 作者：Guodong Li ; Bo Kong ; Yan Zhu ; Le Zhan ; Jessica A. Williams ; Ossama Tawfik ; Karen M. Kassel ; James P. Luyendyk ; Li Wang ; Grace L. Guo
- 关键词：ALT ; alanine aminotransferase ; GP130 ; glycoprotein 130 ; JAK ; Janus kinases ; FXR ; farnesoid X receptor ; FXR&minus ; /&minus ; FXR knockout ; HCC ; hepatocellular carcinoma ; IL-1¦Á ; interleukin-1¦Á ; IL-1¦Â ; interleukin-1¦Â ; IL-6 ; interleukin-6 ; Q-PCR ; quantitat
- 刊名：Toxicology and Applied Pharmacology
- 出版年：2013
- 出版时间：15 October, 2013
- 年：2013
- 卷：272
- 期：2
- 页码：299-305
- 全文大小：1114 K
文摘
Farnesoid X receptor (FXR, Nr1h4) and small heterodimer partner (SHP, Nr0b2) are nuclear receptors that are critical to liver homeostasis. Induction of SHP serves as a major mechanism of FXR in suppressing gene expression. Both FXR?/? and SHP?/? mice develop spontaneous hepatocellular carcinoma (HCC). SHP is one of the most strongly induced genes by FXR in the liver and is a tumor suppressor, therefore, we hypothesized that deficiency of SHP contributes to HCC development in the livers of FXR?/? mice and therefore, increased SHP expression in FXR?/? mice reduces liver tumorigenesis. To test this hypothesis, we generated FXR?/? mice with overexpression of SHP in hepatocytes (FXR?/?/SHPTg) and determined the contribution of SHP in HCC development in FXR?/? mice. Hepatocyte-specific SHP overexpression did not affect liver tumor incidence or size in FXR?/? mice. However, SHP overexpression led to a lower grade of dysplasia, reduced indicator cell proliferation and increased apoptosis. All tumor-bearing mice had increased serum bile acid levels and IL-6 levels, which was associated with activation of hepatic STAT3. In conclusion, SHP partially protects FXR?/? mice from HCC formation by reducing tumor malignancy. However, disrupted bile acid homeostasis by FXR deficiency leads to inflammation and injury, which ultimately results in uncontrolled cell proliferation and tumorigenesis in the liver.