Related Experiment Video
Updated: May 10, 2026
Cell Type-specific Gene Expression Profiling in the Mouse Liver
Published on: September 17, 2019
Small heterodimer partner overexpression partially protects against liver tumor development in farnesoid X receptor
1Department of Surgical Oncology, Cancer Treatment Center, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China.
Abstract:
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(-/-)/SHP(Tg)) 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.
Insights
Farnesoid X receptor (FXR) deficiency leads to liver cancer in mice. Overexpressing small heterodimer partner (SHP) reduced tumor malignancy but did not prevent cancer development.
Area of Science:
- Hepatology
- Molecular Biology
- Oncology
Background:
- Farnesoid X receptor (FXR) and small heterodimer partner (SHP) are crucial nuclear receptors for liver homeostasis.
- FXR regulates SHP, a key suppressor of gene expression and a tumor suppressor.
- Both FXR and SHP deficiencies in mice lead to spontaneous hepatocellular carcinoma (HCC).
Purpose of the Study:
- To investigate the role of SHP in HCC development in FXR-deficient mice.
- To determine if increased SHP expression mitigates liver tumorigenesis in the absence of FXR.
Main Methods:
- Generated and analyzed FXR(-/-) mice with hepatocyte-specific SHP overexpression (FXR(-/-)/SHP(Tg)).
- Assessed liver tumor incidence, size, grade of dysplasia, cell proliferation, and apoptosis.
- Measured serum bile acid and IL-6 levels, and hepatic STAT3 activation.
Main Results:
- Hepatocyte-specific SHP overexpression did not alter liver tumor incidence or size in FXR(-/-) mice.
- SHP overexpression reduced tumor grade, cell proliferation, and increased apoptosis.
- Tumor-bearing mice exhibited elevated serum bile acid and IL-6 levels, linked to STAT3 activation.
Conclusions:
- SHP partially protects FXR(-/-) mice from HCC by reducing tumor malignancy.
- Disrupted bile acid homeostasis in FXR deficiency promotes inflammation and injury, driving liver tumorigenesis.
