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In HFD-fed TG mice, we found no difference in TUNEL staining or activated caspase 3 level in the liver relative to HFD-fed WT mice (data not shown). As expected, hepatocytes were negative for ��-catenin staining in KO mice. However, HFD-fed TG mice frequently had cytoplasmic and nuclear staining for ��-catenin in hepatocytes (Figure?3 and Supplemental Figure?S4). Two well-established ��-catenin target genes, Cyp2E1 and GS, exhibit differential perivenous expression patterns. Cyp2E1 exhibits dynamic zonation, whereas GS exhibits fixed zonation in a narrow rim of perivenous hepatocytes. We found increased intensity of Cyp2E1 staining CP-673451 mw and expansion of the perivenous zone of expression in HFD-fed WT mice ( Figure?3). We observed no hepatic Cyp2E1 staining in KO mice. In chow-fed TG mice, we found that a wider zone of perivenous hepatocytes stained positive for Cyp2E1. In HFD-fed TG mice, Cyp2E1 expression expanded to the midzonal region and strongly correlated with steatosis within hepatocytes ( Figure?3). In contrast to Cyp2E1, we found no difference between chow- and HFD-fed WT mice in the zonal pattern of expression of GS. KO mice did not express GS in the liver. TG mice exhibited more intense GS staining but in a zonal expression pattern that was similar to that in oxyclozanide WT mice ( Figure?3). Consistent with the changes in hepatic GS expression, KO mice exhibited lower and TG mice higher serum glutamine levels on chow and HFD diets compared with WT mice ( Supplemental Figure?S5). On chow diet, WT and TG mice had similar weight and were morphologically Epigenetics inhibitor indistinguishable. However, HFD-fed TG mice gained more weight and at 8 weeks exhibited prominent visceral fat and higher perigonadal fat pad mass compared with WT mice (Figure?4A). On chow diet, KO mice had body weight and visceral fat similar to WT mice. However, HFD-fed KO mice gained less weight and exhibited less prominent visceral fat and lower perigonadal fat pad mass at 4 weeks compared with WT mice (Figure?4B and Supplemental Figure?S6). We next performed metabolic cage experiments with mice fed the HFD for 1 week to acclimatize them to the diet but avoid potential compensatory changes. Compared with WT mice, HFD-fed KO mice exhibited overall higher and TG mice lower respiratory exchange ratio (3%, P?