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Toxicol Appl Pharmacol. 2013 Oct 15;272(2):299-305. doi: 10.1016/j.taap.2013.06.016. Epub 2013 Jun 26.

Small heterodimer partner overexpression partially protects against liver tumor development in farnesoid X receptor knockout mice.

Author information

1
Department 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.

KEYWORDS:

ALT; Bile acids; Chronic injury; FXR; FXR knockout; FXR(−/−); Farnesoid X receptor; GP130; HCC; IL-1α; IL-1β; IL-6; JAK; Janus kinases; Liver tumor; Q-PCR; SHP; SHP knockout; SHP transgenic; SHP(Tg); SHP(−/−); SOCS3; Small heterodimer partner; Tumor malignancy; WT; alanine aminotransferase; farnesoid X receptor; glycoprotein 130; hepatocellular carcinoma; interleukin-1α; interleukin-1β; interleukin-6; quantitative real-time PCR; small heterodimer partner; suppressor of cytokine signaling 3; wild type

PMID:
23811326
PMCID:
PMC4039201
DOI:
10.1016/j.taap.2013.06.016
[Indexed for MEDLINE]
Free PMC Article

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