21 Together, these observations R788 suggest that catabolism of existing adipose stores may be essential for
normal hepatic regeneration. To address this possibility, regeneration was examined in fld mice.22 The fld mice are homozygous for a mutation in Lpin1, which results in markedly diminished adipose tissue depot size throughout the body.22 Strain-matched wild-type and heterozygous mice appear identical to each other and exhibit comparable amounts of total body fat (18% ± 2% and 18% ± 1%, respectively, versus 13% ± 1% in fld mice; assessed by MR spectroscopy). Wild-type and heterozygous mice also demonstrate equivalent hepatocellular proliferation 36 hours after two-thirds partial hepatectomy, the time of peak proliferation in this model (Fig. 4C). Therefore,
heterozygous mice were used as controls for analyses of liver regeneration in fld animals. These experiments showed that the regenerative response to partial hepatectomy was significantly impaired in fld mice, with reduced hepatocellular BrdU incorporation (Fig. 4A-C) and cyclin D1 mRNA and protein expression (Fig. 5A-C) compared to controls. The fld mice also exhibited diminished hepatocellular mitotic frequency (Fig. 2D-F; *P = 0.11 at 48 hours; P = 0.06 at 72 hours) and delayed recovery of liver mass (57% ± 5% versus 62% ± 1% in controls at 72 hours after partial hepatectomy, P = 0.2); Vemurafenib cell line however, these differences were not significant. Postoperative mortality was modestly increased in fld mice with 3 of 42 animals dying within 24 hours after partial hepatectomy compared to 0 of 44 heterozygous controls (P = 0.08). There was no increase in hepatic tissue necrosis in surviving Gefitinib molecular weight null mice compared to controls (Fig. 4D,E). The hepatic regenerative response to CCl4 administration was also investigated, with administration of CCl4 at a dose sufficient to induce robust regeneration in wild-type mice (Fig. 2) resulting in lethality in four of four fld mice versus one of
four controls. Together, these data show that liver regeneration is impaired in lipodystrophic fld mice. Next, changes in systemic metabolism after partial hepatectomy were examined in fld mice. The results showed that regenerating liver from fld mice contained significantly less triglyceride than controls (Fig. 6A). Triglyceride content was also reduced in quiescent fld liver, which likely reflects both the systemic adipose deficiency of fld mice and the increased hepatic triglyceride content at baseline in the BALBc genetic background.23fld mice exhibited less severe hypoglycemia 12-24 hours after partial hepatectomy (Fig. 6B) and higher plasma insulin levels 48-72 hours after surgery (Fig. 6C) compared to controls.