title: mTOR-Dependent Suppression of Remnant Liver Regeneration in Liver Failure After Massive Liver Resection in Rats.
abstract: OBJECTIVE
  Massive hepatectomy often leads to fatal liver failure because of a small remnant liver volume. The aim of this study was to investigate the potential mechanisms leading to liver failure.
  
  
  METHODS
  Sprague-Dawley rats had performed a sham operation, 85 % partial hepatectomy (PH) or 90 % PH, and all had free access to water with or without supplemented glucose. Liver function and survival were evaluated. Liver parenchymal injury was assessed by evaluating hepatic pathology, blood biochemistry, and apoptotic and necrotic alterations. The regeneration response was assessed by the weight gain of the remnant liver, hepatocyte proliferation markers, and regeneration-related molecules.
  
  
  RESULTS
  The 90 % hepatectomy resulted in a significantly lower survival rate and impaired liver function; however, no significant more serious liver parenchymal injuries were detected. TNF-α, HGF, myc and IL-6 were either similarly expressed or overexpressed; however, the increase in remnant liver weight, mitotic index, and the presence of Ki-67 and PCNA were significantly lower in the 90 %-hepatectomized rats. mTOR, p70S6K and 4EBP1 were not activated in the remnant liver after a 90 % hepatectomy as obviously as those after an 85 % hepatectomy, which was concomitant with the higher expression of phospho-AMPK and a lower intrahepatic ATP level. Glucose treatment significantly improved the survival rate of 90 %-hepatectomized rats.
  
  
  CONCLUSIONS
  Suppression of remnant liver regeneration was observed in the 90 % PH and contributed to fatal liver failure. This suppressed liver regenerative capacity was related to the inhibited activation of mTOR signaling.
authors.affiliation: Department and Institute of Hepatobiliary Surgery, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853, China, drzdx@126.com.
authors.forename: Dong Xin
authors.initials: DX
authors.lastname: Zhang
authors.forename: Chong Hui
authors.initials: CH
authors.lastname: Li
authors.forename: Ai Qun
authors.initials: AQ
authors.lastname: Zhang
authors.forename: Shan
authors.initials: S
authors.lastname: Jiang
authors.forename: Yan Hua
authors.initials: YH
authors.lastname: Lai
authors.forename: Xin Lan
authors.initials: XL
authors.lastname: Ge
authors.forename: Ke
authors.initials: K
authors.lastname: Pan
authors.forename: Jia Hong
authors.initials: JH
authors.lastname: Dong
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D024243:HMGB1 Protein / Q000235:genetics; D006498:Hepatectomy / Q000009:adverse effects*; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000737:chemistry / Q000502:physiology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D019394:Ki-67 Antigen / Q000032:analysis; D017093:Liver Failure / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D015996:Survival Rate; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D024243:HMGB1 Protein; D015850:Interleukin-6; D019394:Ki-67 Antigen; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D017228:Hepatocyte Growth Factor; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose