To test this possibility, we investigated liver regeneration in fld mice, which have diminished peripheral adipose stores.22 The PD0325901 cost results showed that early hepatic fat content was reduced and liver regeneration impaired following partial hepatectomy in these animals. The increased insulin levels in fld mice 48-72 hours after partial hepatectomy is consistent with prior characterization of insulin resistance in these animals.24 Furthermore, the increased blood glucose levels 12-24 hours after surgery in fld mice, together with

our previous characterization of the hypoglycemic response to partial hepatectomy and the inhibitory effect of glucose supplementation on early hepatic fat accumulation and liver regeneration in wild-type mice,9 suggest that perturbations in systemic glucose metabolism may contribute to impaired regeneration in fld mice. Indeed, hepatic p21 expression, which is increased by dextrose supplementation,9 was also

augmented in regenerating fld mouse liver. Collectively, these data suggest a model in which the hypoglycemia that follows partial hepatectomy induces systemic lipolysis and accumulation of fat derived from peripheral stores in the early regenerating liver, and that these events provide or regulate essential signals for normal find more liver regeneration. The specific mechanisms responsible for impaired liver regeneration in lipodystrophic fld mice require further elucidation. Future analyses should address whether the requirement for systemic adipose stores during normal MCE liver regeneration is based on adipose as a source of metabolic fuel to support regeneration,38

lipid precursor for new membrane synthesis, a specific signal that initiates the regenerative response itself, or perhaps all of these. Our data showing that circulating levels of adiponectin are markedly reduced in fld mice together with published data demonstrating that adiponectin-null mice exhibit impaired liver regeneration26, 27 raise the possibility that this hormone may be such an essential adipose-derived signal. Because the gene that is mutated in fld mice, Lpin1, is also expressed in liver,22 another important consideration is that absence of hepatic Lpin1 expression might contribute to impaired regeneration in fld mice. In this regard, it is intriguing to consider that the Lpin1 gene product (lipin 1) is bifunctional in liver: It catalyzes an essential step in glycerolipid biosynthesis,39 which may be critical for synthesis of new cell membranes, and also coactivates peroxisome proliferator-activated receptor alpha (PPARα) activity, which is required for normal liver regeneration40, 41 and may be regulated by binding phospholipid.