The studies reported here were undertaken to further characterize

the regulation and functional significance of changes in systemic metabolism during normal liver regeneration. The results show that a systemic catabolic response is induced in each of two distinct models of liver Protease Inhibitor Library regeneration. These experiments also show that catabolism of total and systemic fat mass—like regeneration itself—occurs in proportion to the degree of induced hepatic insufficiency. Surprisingly, catabolism of lean mass was not significantly different after one-third versus two-thirds partial hepatectomy. These data raise an intriguing question about liver:body mass regulation: To what body mass compartment is liver mass proportionately regulated? The answer to this question may offer insight into mechanisms of liver regeneration, and will be the subject of future investigations. Our data provide the first detailed characterization of systemic metabolic changes in these classic models of liver regeneration, and the findings reported here also offer insight into previously published analyses of liver regeneration. For example, tumor necrosis

factor α and interleukin-6 have each been identified as essential regulators of normal liver regeneration after partial http://www.selleckchem.com/products/bay-57-1293.html hepatectomy and CCl4 administration,15, 16, 33–36 and also induce cachexia.37 Thus, the catabolic response to liver injury in these models of liver regeneration may be induced by signals that are required for normal regeneration. Together, these considerations raise the possibility that the requirement of such signals for recovery of liver mass following hepatic injury may be mediated by the catabolic

response they induce. We and others have reported that interventions associated with disruption of transient hepatic accumulation of fat during early liver regeneration, including genetic disruption of caveolin-1 or hepatic glucocorticoid receptor expression, and leptin or propranolol supplementation, are associated with impaired regeneration.8, 19, 20 Subsequent analyses by Newberry et al.21 showed that regeneration is not impaired in mice in which dietary uptake of 上海皓元医药股份有限公司 fat or de novo hepatic synthesis of fatty acid is disrupted (intestine-specific microsomal triglyceride transfer protein-null and liver-specific fatty acid synthase-null mice, respectively. That study also showed that regeneration is unaffected in liver fatty acid binding protein-null mice. In each case, the regenerating livers accumulated triglyceride fat but to a lesser extent than controls,21 leading those investigators to speculate on the existence of a critical “threshold of adaptive lipogenesis” that was not crossed in those animal models. Whether the genetic interventions evaluated in the Newberry study affected systemic adipose stores was not reported.