The data described above, together with our previous characterization of the inhibitory effect of supplemental glucose on liver

regeneration,9 suggest LGK-974 clinical trial that perturbations in systemic glucose metabolism may contribute to suppressed regeneration in fld mice. The impaired regenerative response associated with dextrose supplementation was characterized by augmented expression of CCAAT/enhancer binding protein alpha (C/EBPα), p21, and p27.9 Therefore, hepatic expression of these factors was compared between fld and control mice. The results showed that C/EBPα and C/EBPβ mRNA and p27 protein expression were comparable in fld and controls (Supporting Fig. 2 and Fig. 5D-F); however, p21 protein was increased in fld liver (Fig. 5D-F). These data raise the possibility that dysregulated p21 expression contributes to impaired regeneration in fld mice. The adipose-derived

hormones adiponectin and leptin have each been identified as regulators of liver regeneration.13, 25–29 To investigate whether deficiency of either hormone might contribute to impaired regeneration in fld mice, plasma levels of each were determined before and after partial hepatectomy in fld and control mice. This analysis showed that circulating adiponectin and leptin levels were significantly lower in fld animals at baseline (Fig. 7A-C). Following partial hepatectomy, leptin levels declined in controls and remained low in fld mice (Fig. 7C). Because leptin deficiency is associated with impaired liver regeneration,13, 28, 30 the effect of leptin supplementation

Astemizole on regeneration in fld mice was investigated. BGB324 concentration This analysis showed that a regimen of leptin supplementation sufficient to rescue impaired regeneration in CCl4-treated ob/ob mice13 did not augment and, in fact, suppressed hepatocellular proliferation 36 hours after partial hepatectomy in fld mice compared to untreated fld mice and leptin-treated controls (Supporting Fig. 3). Adiponectin levels increased after partial hepatectomy in controls (Fig. 7B), but remained almost undetectable in fld mice (Fig. 7A,B). These data suggest that impaired liver regeneration in fld mice may be mechanistically related to that recently described in adiponectin-null mice.26 Diminished activation of signal transducer and activator of transcription 3 (STAT3) and augmented induction of expression of suppressor of cytokine signaling 3 (SOCS3) were observed in liver after partial hepatectomy in those animals.27 Therefore, STAT3 activation and SOCS3 expression, each of which modulate liver regeneration,31, 32 were quantified after partial hepatectomy in fld and control animals. The results showed comparable STAT3 phosphorylation in both groups; however, the ratio of phosphorylated:total STAT3 was reduced. Moreover, in contrast to the analysis of adiponectin-null mice,27 hepatic SOCS3 expression after partial hepatectomy was significantly lower in fld mice than in controls (Fig.