title: Lipid overloading during liver regeneration causes delayed hepatocyte DNA replication by increasing ER stress in mice with simple hepatic steatosis.
abstract: OBJECTIVE
  Impaired fatty liver regeneration has already been reported in many genetic modification models. However, in diet-induced simple hepatic steatosis, which showed similar phenotype with clinical pathology, whether liver regeneration is impaired or not remains unclear. In this study, we evaluated liver regeneration in mice with diet-induced simple hepatic steatosis, and focused on excess lipid accumulation occurring during liver regeneration.
  
  
  METHODS
  Mice were fed high fat diet (HFD) or control diet for 9-10 weeks. We analyzed intrahepatic lipid accumulation, DNA replication, and various signaling pathways including cell proliferation and ER stress during liver regeneration after partial hepatectomy. In addition, some of mice were pretreated with tauroursodeoxycholic acid (TUDCA), a chemical chaperone which alleviates ER stress, and then we estimated TUDCA effects on liver regeneration.
  
  
  RESULTS
  The peak of hepatocyte BrdU incorporation, the expression of proliferation cell nuclear antigen (PCNA) protein, and the expressions of cell cycle-related genes were observed in delayed time in HFD mice. The expression of phosphorylated Erk1/2 was also delayed in HFD mice. The amounts of liver triglyceride were at least twofold higher in HFD mice at each time point. Intrahepatic palmitic acid was increased especially in HFD mice. ER stress induced during liver regeneration was significantly higher in HFD mice. In HFD mice, pretreatment with TUDCA reduced ER stress and resulted in improvement of delayed liver regeneration.
  
  
  CONCLUSIONS
  In simple hepatic steatosis, lipid overloading occurring during liver regeneration might be caused ER stress and results in delayed hepatocyte DNA replication.
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, 2-2 K1, Yamada-oka, Suita, Osaka, 565-0871, Japan.
authors.forename: Mina
authors.initials: M
authors.lastname: Hamano
authors.forename: Hisao
authors.initials: H
authors.lastname: Ezaki
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kiso
authors.forename: Kunimaro
authors.initials: K
authors.lastname: Furuta
authors.forename: Mayumi
authors.initials: M
authors.lastname: Egawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Kizu
authors.forename: Norihiro
authors.initials: N
authors.lastname: Chatani
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kamada
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Yoshida
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Takehara
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002756:Cholagogues and Choleretics / Q000494:pharmacology; D056751:Cyclin A2 / Q000235:genetics; D056744:Cyclin B1 / Q000235:genetics; D019938:Cyclin D1 / Q000235:genetics; D016213:Cyclins / Q000235:genetics; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000235:genetics; D059305:Diet, High-Fat / Q000009:adverse effects*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000502:physiology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005234:Fatty Liver / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology* / Q000601:surgery; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000235:genetics; D006498:Hepatectomy; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism; D008115:Liver Regeneration / Q000187:drug effects / Q000235:genetics; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size; D010766:Phosphorylation; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D013312:Stress, Physiological; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics; D056811:Unfolded Protein Response; D019892:eIF-2 Kinase / Q000235:genetics
chemical_list: D002756:Cholagogues and Choleretics; D056751:Cyclin A2; D056744:Cyclin B1; D019938:Cyclin D1; D016213:Cyclins; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D006360:Heat-Shock Proteins; D018809:Proliferating Cell Nuclear Antigen; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D000071701:Regulatory Factor X Transcription Factors; D013655:Taurochenodeoxycholic Acid; D014157:Transcription Factors; D019892:eIF-2 Kinase; C503689:Ccne2 protein, mouse; C491524:Foxm1 protein, mouse; C031655:ursodoxicoltaurine