ZBTB20 regulates EGFR expression and hepatocyte proliferation in mouse liver regeneration.

Liver has a unique regenerative capacity, however, its regulatory mechanism is not fully defined. We have established the zinc-finger protein ZBTB20 as a key transcriptional repressor for alpha-fetoprotein (AFP) gene in liver. As a marker of hepatic differentiation, AFP expression is closely associated with hepatocyte proliferation. Unexpectedly, here we showed that ZBTB20 acts as a positive regulator of hepatic replication and is required for efficient liver regeneration. The mice specifically lacking ZBTB20 in hepatocytes exhibited a remarkable defect in liver regeneration after partial hepatectomy, which was characterized by impaired hepatocyte proliferation along with delayed cyclin D1 induction and diminished AKT activation. Furthermore, we found that epithelial growth factor receptor (EGFR) expression was dramatically reduced in the liver in the absence of ZBTB20, thereby substantially attenuating the activation of EGFR signaling pathway in regenerating liver. Adenovirus-mediated EGFR overexpression in ZBTB20-deficient hepatocytes could largely restore AKT activation in response to EGFR ligands in vitro, as well as hepatocyte replication in liver regeneration. Furthermore, ZBTB20 overexpression could significantly restore hepatic EGFR expression and cell proliferation after hepatectomy in ZBTB20-deficient liver. Taken together, our data point to ZBTB20 as a critical regulator of EGFR expression and hepatocyte proliferation in mouse liver regeneration, and may serve as a potential therapeutic target in clinical settings of liver regeneration.

Association of SLC30A8 gene polymorphism with type 2 diabetes, evidence from 46 studies: a meta-analysis.

The solute carrier family 30 member 8 (SLC30A8) gene may be involved in the development of type 2 diabetes mellitus (T2DM) through disrupting ß-cell function. The aim of this study was to assess the association between SLC30A8 rs13266634 polymorphism and susceptibility to T2DM. We searched all reports regarding the association between SLC30A8 rs13266634 polymorphism and T2DM risk through Pubmed, Embase, and the Cochrane Library for English language reports and Chongqing VIP database, Wanfang data, CBMDisc, and CNKI for Chinese language studies. Allelic and genotype comparisons between cases and controls were evaluated, and odds ratios with 95 % confidence intervals were used to assess the strength of their association. A random effects model was selected. Publication bias was estimated using Begg's test. Forty-six studies were included in the analysis with a total of 71,890 cases and 96,753 controls. This meta-analysis suggests that SLC30A8 (rs13266634) polymorphism was associated with T2DM risk. Although previous meta-analyses have shown that this association was only found in Asian and European groups, and not in African populations, our analysis revealed the deleterious effect of SLC30A8 rs13266634 on T2DM in an African population when stratified by ethnicity under additive model even with a small number of studies.

Zbtb20 regulates the terminal differentiation of hypertrophic chondrocytes via repression of Sox9.

The terminal differentiation of hypertrophic chondrocytes is a tightly regulated process that plays a pivotal role in endochondral ossification. As a negative regulator, Sox9 is essentially downregulated in terminally differentiated hypertrophic chondrocytes. However, the underlying mechanism of Sox9 silencing is undefined. Here we show that the zinc finger protein Zbtb20 regulates the terminal differentiation of hypertrophic chondrocytes by repressing Sox9. In the developing skeleton of the mouse, Zbtb20 protein is highly expressed by hypertrophic chondrocytes from late embryonic stages. To determine its physiological role in endochondral ossification, we have generated chondrocyte-specific Zbtb20 knockout mice and demonstrate that disruption of Zbtb20 in chondrocytes results in delayed endochondral ossification and postnatal growth retardation. Zbtb20 deficiency caused a delay in cartilage vascularization and an expansion of the hypertrophic zone owing to reduced expression of Vegfa in the hypertrophic zone. Interestingly, Sox9, a direct suppressor of Vegfa expression, was ectopically upregulated at both mRNA and protein levels in the late Zbtb20-deficient hypertrophic zone. Furthermore, knockdown of Sox9 greatly increased Vegfa expression in Zbtb20-deficient hypertrophic chondrocytes. Our findings point to Zbtb20 as a crucial regulator governing the terminal differentiation of hypertrophic chondrocytes at least partially through repression of Sox9.

[Time-course effect and region-specificity of endoplasmic reticulum stress in rat brains acutely exposed by methylmercury].

OBJECTIVE: To explore time-course effect and region-specificity of endoplasmic reticulum stress in rat brain acutely exposed by methylmercury (MeHg). METHODS: Forty-two SD rats were randomly divided into seven groups, and the rats intraperitoneally injected at the dose of 4 mg/kg bw. MeHg were decapitated at the times of 0.5, 1, 3, 6, 12 and 24 h, then rats in control group intraperitoneally injected by the corresponding volume of normal saline were decapitated. The cerebellum, cerebral cortex, brain stem, hippocampus and striatum were dissected out and weighted on ice at once. The expressions of Grp78 protein which is a marker of endoplasmic reticulum stress, were determined by Western blotting analysis. The contents of reduced glutathione (GSH) of cerebral cortex were also determined. RESULTS: After exposure to MeHg, the tendencies of expression of Grp78 were consistent in various brain regions. It began to increase at the time of 0.5 h and the peak levels reached at the times of 6 h or 12 h, then it began to decline. All expression levels returned nearly to the control levels at the time of 24h. The alternations of Grp78 protein in cerebral cortex and brain stem were statistically significant in comparison with those of control groups at the time of 0h among brain regions. Increases of Grp78 protein in cerebral cortex reached peak levels at the time of 6h after MeHg exposure, and the expressions of Grp78 protein corresponded to 150% of control levels. Increases of Grp78 protein in brain stem reached peak levels at the time of 12 h after MeHg exposure, and the expressions of Grp78 protein corresponded to 140% of control levels. Further, the contents of GSH in cerebral cortex showed the tendencies of first decreases and then gradually showed increases. These changes were inversely correlated to the change of Grp78 protein in cerebral cortex (r = -0.77). CONCLUSION: Rats acutely exposed with MeHg could show endoplasmic reticulum stress in a time dependent and region-specific pattern, and this alteration could be associated with oxidative stress in cerebral cortex.