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Total parenteral nutrition (TPN) is associated with cholestasis and hepatic steatosis in human infants. The present study focused on the changes in hepatic xenobiotic transporters associated with overdose of fat-free or fat-containing TPN in infant rats. Three-week-old male Sprague-Dawley rats were divided into three groups: group 1 received an oral diet, group 2 received TPN without fat, and group 3 received TPN with 20% of its calories from fat (soybean oil emulsion). After TPN administration for 4 days, both serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, which are indicators of hepatic dysfunction, in group 2 were significantly higher (p<0.001) than those in the other groups, whereas there were no differences between groups 1 and 3 in either serum AST or ALT levels. The serum bilirubin concentration in group 2 was also markedly higher than that in the other groups. Mdr2, Bsep, Mrp2, Mrp6, Oct1, and Oat2 mRNA levels were decreased in group 2 (fat-free TPN) compared with those in group 1 (oral diet), whereas Mdr1b, Mrp1, and Mrp5 mRNA levels were increased. Specifically, the level of Mdr1b mRNA in group 2 was 16 times higher (p<0.001) than that in group 1. On the other hand, the changes in these mRNA expression levels in group 3 (fat-containing TPN) were smaller than those in group 2, and specifically, the expression levels of Mdr1b, Mrp1, Mrp5, Mrp6, and Oat2 mRNA in group 3 were not significantly different from those in group 1. The results of the present study indicate that including fat in the TPN regimen is very important in preventing the mRNA up- and down-regulation of xenobiotic transporters, which is considered to be the main factor responsible for the abnormal hepatic changes such as cholestasis associated with the excessive administration of fat-free TPN.

�e previousl� demonstrated that retinoic acid �RA� induces epidermis to transdifferen�e previousl� demonstrated that retinoic acid �RA� induces epidermis to transdifferentiate to mucosal epithelium with goblet cells in chick embr�onic cultured skin. To characterize the molecular mechanism of this transdifferentiation process, we used rat embr�onic cultured skin and immunohistochemistr� to confirm that RA-induced epidermal transdifferentiation accompanies the expression of markers of esophagus epithelium. Because Gbx1, TG2/Gh �transglutaminase2� and TGF-b2 are reported individuall� to be induced b� RA in cultures of chick embr�onic skin, mouse epidermal cells and human hair follicles respectivel�, here, we investigated whether cooperative interpla� of Gbx1, TG2/Gh and TGF-b2 is required for the transdifferentiation of epidermal cells to mucosal cells. �e have shown that expression of Gbx1, TG2/Gh and TGF-b proteins were all upregulated in RA-induced transdifferentiated skin and that the former two were expressed in the epidermis, while TGF-b was expressed in the dermis. Inhibitors of the TGF-b signal pathwa� partiall� inhibited transdifferentiation. Overexpression of both hTG2/Gh and mGbx1 together in the epidermis b� electroporation resulted in cuboidal cells in the upper cell la�ers of the epidermis without keratinized la�ers, although epidermal keratinization was observed in skin b� overexpression of either of them. Labeling DNA with BrdU indicated that RA directl� transdifferentiated transient amplif�ing epidermal cells, not stem cells, to mucosal cells. This stud� showed that coexpression of TG/2 and Gbx1 in the epidermis was required for esophagus-like mucosal transdifferentiation, and that increase in TGF-b2 expression b� RA in the dermis was essential to induce transdifferentiation through epithelial-mesench�mal interaction.

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