Deregulation of growth factor, circadian clock, and cell cycle signaling in regenerating hepatocyte RXRα-deficient mouse livers

Xiaoxia Yang, Minglei Guo, Yu Jui Yvonne Wan

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Activation of the nuclear receptors constitutive androstane receptor, pregnane X receptor, and peroxisome proliferator-activated receptor α results in hepatomegaly, and these nuclear receptors are implicated in the regulation of liver regeneration. Retinoid X receptor (RXR)α is an essential partner of these nuclear receptors. Therefore, we studied the role of hepatocyte RXRα in liver regeneration using partial hepatectomy model. The results showed that hepatocyte RXRα deficiency caused an approximately 20-hour delay in hepatocyte proliferation after partial hepatectomy. Several pathways, including growth factors and the circadian cell cycle, were impaired due to hepatocyte RXRα deficiency. In addition, the expression patterns of hepatocyte growth factor, fibroblast growth factor 2, platelet-derived growth factor, and transforming growth factor α were altered due to lack of RXRα. Furthermore, the peroxisome proliferatoractivated receptor α/brain and muscle Arnt-like protein 1/Rev-erbα/P21 pathway was compromised, and Cry1/Cry2 and Wee1/Per1 expression was deregulated in regenerating RXRα-null livers. Accordingly, the expression and regulation of cyclin D1/Cyclindependent Kinase (Cdk)4, cyclin E1/Cdk2, cyclin A2/ Cdk2, and cyclin B1/Cdk1 after partial hepatectomy were altered in regenerating RXRα-null livers. Hepatocyte RXRα deficiency also affected the basal, as well as regeneration-induced cyclin E1 expression levels. Activation of RXRα by retinoic acids increased the cyclin E1 promoter activity indicating retinoic acidmediated signaling positively controls cyclin E1 gene expression. As many of these observed changes were not documented in the regenerating livers of other nuclear receptor knockout mice, these observed effects may be hepatocyte RXRα specific.

Original languageEnglish (US)
Pages (from-to)733-743
Number of pages11
JournalAmerican Journal of Pathology
Volume176
Issue number2
DOIs
StatePublished - Feb 2010

Fingerprint

Retinoid X Receptors
Circadian Clocks
Hepatocytes
Intercellular Signaling Peptides and Proteins
Cell Cycle
Liver
Cyclins
Cytoplasmic and Nuclear Receptors
Hepatectomy
Liver Regeneration
Cyclin A2
rev Gene Products
Cyclin B1
Peroxisome Proliferator-Activated Receptors
Peroxisomes
Hepatomegaly
Hepatocyte Growth Factor
Cyclin D1
Platelet-Derived Growth Factor
Transforming Growth Factors

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Deregulation of growth factor, circadian clock, and cell cycle signaling in regenerating hepatocyte RXRα-deficient mouse livers. / Yang, Xiaoxia; Guo, Minglei; Wan, Yu Jui Yvonne.

In: American Journal of Pathology, Vol. 176, No. 2, 02.2010, p. 733-743.

Research output: Contribution to journalArticle

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