Postponing the Hypoglycemic Response to Partial Hepatectomy Delays Mouse Liver Regeneration

Abstract

All serious liver injuries alter metabolism and initiate hepatic regeneration. Recent studies using partial hepatectomy (PH) and other experimental models of liver regeneration implicate the metabolic response to hepatic insufficiency as an important source of signals that promote regeneration. Based on these considerations, the analyses reported here were undertaken to assess the impact of interrupting the hypoglycemic response to PH on liver regeneration in mice. A regimen of parenteral dextrose infusion that delays PH-induced hypoglycemia for 14 hours after surgery was identified, and the hepatic regenerative response to PH was compared between dextrose-treated and control mice. The results showed that regenerative recovery of the liver was postponed in dextrose-infused mice (versus vehicle control) by an interval of time comparable to the delay in onset of PH-induced hypoglycemia. The regulation of specific liver regeneration-promoting signals, including hepatic induction of cyclin D1 and S-phase kinase-associated protein 2 expression and suppression of peroxisome proliferator-activated receptor γ and p27 expression, was also disrupted by dextrose infusion. These data support the hypothesis that alterations in metabolism that occur in response to hepatic insufficiency promote liver regeneration, and they define specific pro- and antiregenerative molecular targets whose regenerative regulation is postponed when PH-induced hypoglycemia is delayed.

Targeting β‐catenin in hepatocellular cancers induced by coexpression of mutant β‐catenin and K‐Ras in mice

“…However, a dramatic decrease in cyclin‐D1 staining was evident after one and two cycles of CTNNB1‐LNP whereas its staining was more midzonal after three cycles, similar to its normal localization in adult mice (Fig. B) …”

Update on the Mechanisms of Liver Regeneration

“…Intriguingly, dextrose supplementation led to decreased activation of Tcf4, a β-catenin binding transcription factor, and subsequent reduction in cyclin-D1 expression, DNA replication, and liver-weight-to-body-weight ratio. 64 Collectively, these data support previous findings that the in vitro addition of amino acids to hepatocytes induces cyclin-D1, and protein deprivation prevents cyclin-D1 expression in vitro and in vivo. 65 The LR process thus integrates the processes of metabolism and proliferation and may be a chief cellular process initiating LR.…”

PTEN Down‐Regulation Promotes β‐Oxidation to Fuel Hypertrophic Liver Growth After Hepatectomy in Mice

“…Altogether, these results suggest that the expanded TRAS period in PtenKO results neither from increased lipogenesis nor from elevations in active lipid import. Rather, the systemic redistribution of lipids into liver after tissue loss may be enhanced because of an elevated mobilization of peripheral fats pre‐existing in PtenKO liver before PH . Given that FGF21 can increase hepatic energy expenditure, the expanded TRAS period might further relate to a prolonged catabolic phase in regenerating PtenKO liver.…”