TY - JOUR
T1 - Postponing the hypoglycemic response to partial hepatectomy delays mouse liver regeneration
AU - Huang, Jiansheng
AU - Schriefer, Andrew E.
AU - Cliften, Paul F.
AU - Dietzen, Dennis
AU - Kulkarni, Sakil
AU - Sing, Sucha
AU - Monga, Satdarshan P.S.
AU - Rudnick, David A.
N1 - Funding Information:
Supported by the Children''s Discovery Institute of Washington University and St. Louis Children''s Hospital (SLCH; D.A.R.); the Department of Pediatrics, Washington University School of Medicine (WUSM); an unrestricted donation from Karsyn''s Kause Foundation (D.A.R.); WUSM Digestive Disease Research Core Center grant NIH-NIDDK P30-DK52574; NIH grants 1RO1DK62277 and 1RO1DK100287; and an Endowed Chair for Experimental Pathology (S.P.S.M.). The Genome Technology Access Center, Department of Genetics, WUSM, is partially funded by NCI Cancer Center grant P30CA91842 to the Siteman Cancer Center and ICTS/CTSA (Institute of Clinical and Translational Sciences/Clinical and Translational Science Awards) grant UL1TR000448 from the National Center for Research Resources, a component of the NIH, and NIH Roadmap for Medical Research.
Publisher Copyright:
© Copyright 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
PY - 2016/3/1
Y1 - 2016/3/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84958984989&partnerID=8YFLogxK
U2 - 10.1016/j.ajpath.2015.10.027
DO - 10.1016/j.ajpath.2015.10.027
M3 - Article
C2 - 26772417
AN - SCOPUS:84958984989
SN - 0002-9440
VL - 186
SP - 587
EP - 599
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 3
ER -