Effects of α-tocopherol supplementation on liver of rats chronically exposed to ethanol.

BACKGROUND/AIMS: Chronic alcoholism is characterized by hepatotoxicity associated with antioxidant and redox status imbalance. Continuous ethanol intake induces free radical synthesis, resulting in the depletion of antioxidants, especially α-tocopherol, which has an important role in lipid peroxidation. This study aimed to evaluate if α-tocopherol supplementation can restore liver phenotype in rats chronically exposed to ethanol. METHODS: α-Tocopherol levels were determined and histologic analysis of liver was performed. Hepatic gene expression was analyzed through oligonucleotide microarray and real-time PCR. RESULTS: Alcohol exposure for 6 weeks did not decrease hepatic α-tocopherol levels; however, both groups exposed to ethanol (supplemented or not with α-tocopherol) displayed fatty liver. The antioxidant supplementation prevented Mallory bodies and inflammatory infiltration, but not apoptosis, in liver of the rats exposed to ethanol. Gene expression analysis showed evidence of adaptive response to chronic alcohol consumption, where antioxidant components were not regulated. Nevertheless, differentially expressed genes reflected the change in cellular homeostasis. CONCLUSION: The hepatic α-tocopherol content was coherent with the antioxidant gene expression in this study. Cells are likely to have adapted and restored their antioxidant status after long-term ethanol exposure, which might be the reason for such conflicting reports concerning α-tocopherol status in chronic alcoholism.

Novel molecular pathways elicited by mutant FGFR2 may account for brain abnormalities in Apert syndrome.

Apert syndrome (AS), the most severe form craniosynostosis, is characterized by premature fusion of coronal sutures. Approximately 70% of AS patients carry S252W gain-of-function mutation in FGFR2. Besides the cranial phenotype, brain dysmorphologies are present and are not seen in other FGFR2-asociated craniosynostosis, such as Crouzon syndrome (CS). Here, we hypothesized that S252W mutation leads not only to overstimulation of FGFR2 downstream pathway, but likewise induces novel pathological signaling. First, we profiled global gene expression of wild-type and S252W periosteal fibroblasts stimulated with FGF2 to activate FGFR2. The great majority (92%) of the differentially expressed genes (DEGs) were divergent between each group of cell populations and they were regulated by different transcription factors. We than compared gene expression profiles between AS and CS cell populations and did not observe correlations. Therefore, we show for the first time that S252W mutation in FGFR2 causes a unique cell response to FGF2 stimulation. Since our gene expression results suggested that novel signaling elicited by mutant FGFR2 might be associated with central nervous system (CNS) development and maintenance, we next investigated if DEGs found in AS cells were also altered in the CNS of an AS mouse model. Strikingly, we validated Strc (stereocilin) in newborn Fgfr2(S252W/+) mouse brain. Moreover, immunostaining experiments suggest a role for endothelial cells and cerebral vasculature in the establishment of characteristic CNS dysmorphologies in AS that has not been proposed by previous literature. Our approach thus led to the identification of new target genes directly or indirectly associated with FGFR2 which are contributing to the pathophysiology of AS.