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

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.

SUBMITTER: Li G

PROVIDER: S-EPMC4039201 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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

Li Guodong G Kong Bo B Zhu Yan Y Zhan Le L Williams Jessica A JA Tawfik Ossama O Kassel Karen M KM Luyendyk James P JP Wang Li L Guo Grace L GL

Toxicology and applied pharmacology 20130626 2

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 FX ...[more]

PMID: 23811326

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Project description:In mammals, circadian rhythms are essential for coordinating the timing of various metabolic processes. The Clock gene regulates diurnal plasma triglyceride fluctuation through nuclear receptor small heterodimer partner (Shp; Nr0b2). Given that SHP is a critical regulator of metabolism in the liver, it is unknown whether SHP is necessary to coordinate metabolism and circadian rhythms. Shp(+/+) and Shp(-/-) mice on a C57BL/6 background (n = 3-5/group) were fed a standard chow diet and water ad libitum. Serum and livers were collected at zeitgeber time 2, 6, 10, 14, 18, and 22. In vivo and in vitro assays included RNA sequencing, quantitative polymerase chain reaction, very-low-density lipoprotein production, adenovirus overexpression and small interfering RNA knockdown, serum parameters, circadian locomotor activity, Oil Red O staining, transient transfection, luciferase reporter assay, chromatin immunoprecipitation assay, gel-shift assay, coimmunoprecipitation, and western blottings. Shp deficiency had a robust global impact on major liver metabolic genes. Several components of the liver clock, including peroxisome proliferator-activated receptor-?, coactivator 1 (Pgc-1?), neuronal PAS domain-containing protein 2 (Npas2), and retinoic acid-related orphan receptor (Ror)?/? were sharply induced in Shp(-/-) liver. At the molecular level, SHP inhibited Npas2 gene transcription and promoter activity through interaction with Ror? to repress Ror? transactivation and by interacting with Rev-erb? to enhance its inhibition of Ror? activity. Conversely, Npas2 controlled the circadian rhythm of Shp expression by binding rhythmically to the Shp promoter, which was enhanced by nicotinamide adenine dinucleotide, but not nicotinamide adenine dinucleotide phosphate. Phenotypically, Npas2 deficiency induced severe steatosis in Shp(-/-) mice, which was attributed to the dysregulation of lipoprotein metabolism.Shp and Npas2 crosstalk is essential to maintain hepatic lipid homeostasis.

Dataset Information

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

Publications

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

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