Hepatocyte homeostasis for chromosome ploidization and liver function is regulated by Ssu72 protein phosphatase.

UNLABELLED: Hepatocyte chromosome polyploidization is an important feature of liver development and seems to be required for response to liver stress and injury signals. However, the question of how polyploidization can be tightly regulated in liver growth remains to be answered. Using a conditional knockout mouse model, liver-specific depletion of Ssu72 protein phosphatase was found to result in impairment in regulation of polyploidization. Interestingly, the aberrant polyploidization in Ssu72-depleted mice was associated with impaired liver damage response and increased markers of liver injury and seemed to mimic the phenotypic features of liver diseases such as fibrosis, steatosis, and steatohepatitis. In addition, depletion of Ssu72 caused deregulation of cell cycle progression by overriding the restriction point of the cell cycle and aberrantly promoting DNA endoreplication through G2 /M arrest. CONCLUSION: Ssu72 plays a substantial role in the maintenance of hepatic chromosome homeostasis and would allow monitoring of liver function.

Targeted disruption of Mcm10 causes defective embryonic cell proliferation and early embryo lethality.

Minichromosome maintenance 10 (MCM10) is a conserved, abundant nuclear protein, which plays a key role in the initiation of eukaryotic chromosomal DNA replication and elongation. To elucidate the physiological importance of MCM10 in vivo, we generated conventional knockout mice. No MCM10-null embryos were recovered after E8.5, and the mutation was found to be lethal before the implantation stage. Mutant embryos showed apparently normal growth until the morula stage, but growth defects after this stage. The dramatic reduction of 5-bromo-2-deoxyuridine (BrdU) incorporation in the mutant embryo, followed by cell death, suggests that defective cell proliferation may underlie this developmental failure. Taken together, these findings provide the first unequivocal genetic evidence for an essential and non-redundant physiological role of MCM10 during murine peri-implantation development.

Deletion of exons 3 and 4 in the mouse Nr1d1 gene worsens high-fat diet-induced hepatic steatosis.

AIMS: To elucidate the role of nuclear receptor subfamily 1, group D, member 1 (Nr1d1) in hepatic lipid metabolism and pathogenesis of nonalcoholic fatty liver diseases, Nr1d1 gene mutant mice, in which the DNA-binding domain (exons 3 and 4) was deleted (Nr1d1 Δex3/4), were challenged with a high-fat diet (HFD), and the gene expression patterns that responded to this alteration were profiled. MAIN METHODS: The Nr1d1 Δex3/4 mice were fed an HFD for 12weeks. Liver tissues were examined by histology, and lipid droplets were detected by Oil-Red O staining. Serum biochemical analyses were performed to assess markers of liver injury. Microarray analysis was used to profile hepatic gene expression patterns. Functional annotation, upstream prediction, and gene coexpression prediction analyses were performed. KEY FINDINGS: The Nr1d1 Δex3/4 mice showed enhanced hepatic steatosis after being challenged with an HFD, but not with a low-fat diet, indicating an interaction between diet and genotype for this phenotypic change. Gene expression profiling revealed that this interaction might involve neutrophil recruitment and the cyclic adenosine monophosphate metabolic pathway. A study of transcription factor binding site enrichment suggested that CCAAT/enhancer-binding protein alpha and hepatocyte nuclear factor 4 alpha were associated with this phenotypic change. SIGNIFICANCE: Loss of DNA binding of Nr1d1 was associated with a deterioration in hepatic steatosis. The interaction between the Nr1d1 Δex3/4 genotype with an HFD might mediate these phenotypic changes, probably through a nonclassical transcriptional function of Nr1d1.