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.