کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5846638 | 1128495 | 2013 | 7 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Small heterodimer partner overexpression partially protects against liver tumor development in farnesoid X receptor knockout mice Small heterodimer partner overexpression partially protects against liver tumor development in farnesoid X receptor knockout mice](/preview/png/5846638.png)
- SHP does not prevent HCC incidence nor size in FXR KO mice but reduces malignancy.
- Increased SHP promotes apoptosis.
- Bile acids and inflammation maybe critical for HCC formation with FXR deficiency.
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 FXRâ/â and SHPâ/â 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 FXRâ/â mice and therefore, increased SHP expression in FXRâ/â mice reduces liver tumorigenesis. To test this hypothesis, we generated FXRâ/â mice with overexpression of SHP in hepatocytes (FXRâ/â/SHPTg) and determined the contribution of SHP in HCC development in FXRâ/â mice. Hepatocyte-specific SHP overexpression did not affect liver tumor incidence or size in FXRâ/â 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 FXRâ/â 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.
Journal: Toxicology and Applied Pharmacology - Volume 272, Issue 2, 15 October 2013, Pages 299-305