title: Accelerated partial hepatectomy-induced liver cell proliferation is associated with liver injury in Nur77 knockout mice.
abstract: Nur77, encoded by Nr4a1 (alias Nur77), plays roles in cell death, survival, and inflammation. To study the role of Nur77 in liver regeneration, wild-type (WT) and Nur77 knockout (KO) mice were subjected to standard two-thirds partial hepatectomy (PH). Nur77 mRNA and protein levels were markedly induced at 1 hour after PH in WT livers, coinciding with ERK1/2 activation. Surprisingly, Nur77 KO mice exhibited a higher liver-to-body weight ratio than WT mice at 24, 48, and 72 hours after PH. Nur77 KO livers exhibited increase in Ki-67-positive hepatocytes at 24 hours, with early induction of cell-cycle genes. Despite accelerated regeneration, Nur77 KO livers paradoxically incurred necrosis, hepatocyte apoptosis, elevated serum alanine aminotransferase activity, and Kupffer cell accumulation. Microarray analysis revealed up-regulation of genes modulating inflammation, cell proliferation, and apoptosis but down-regulation (due to Nur77 deficiency) of glucose and lipid homeostasis genes. Levels of proinflammatory cytokines IL-6, IL-12, IL-23, and CCL2 were increased and levels of anti-inflammatory IL-10 were decreased, compared with WT. Activated NF-κB and STAT3 and mRNA levels of target genes Myc and Bcl2l1 were elevated in Nur77 KO livers. Overall, Nur77 appears essential for regulating early signaling of liver regeneration by modulating cytokine-mediated inflammatory, apoptotic, and energy mobilization processes. The accelerated liver regeneration observed in Nur77 KO mice is likely due to a compensatory effect caused by injury.
authors.affiliation: Department of Medical Pathology and Laboratory Medicine, University of California, Davis Health Systems, Sacramento, California.
authors.forename: Ying
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China; Guangzhou Digestive Disease Center, Guangzhou, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhan
authors.affiliation: Department of Medical Pathology and Laboratory Medicine, University of California, Davis Health Systems, Sacramento, California.
authors.forename: Hui-Xin
authors.initials: HX
authors.lastname: Liu
authors.affiliation: Department of Medical Pathology and Laboratory Medicine, University of California, Davis Health Systems, Sacramento, California.
authors.forename: Thinh
authors.initials: T
authors.lastname: Chau
authors.affiliation: Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China; Guangzhou Digestive Disease Center, Guangzhou, China.
authors.forename: Yuyuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Medical Pathology and Laboratory Medicine, University of California, Davis Health Systems, Sacramento, California; Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China; Guangzhou Digestive Disease Center, Guangzhou, China. Electronic address: yjywan@ucdavis.edu.
authors.forename: Yu-Jui
authors.initials: YJ
authors.lastname: Wan
authors.forename: Yu-Jui
authors.initials: YJ
authors.lastname: Yvonne Wan
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001835:Body Weight; D049109:Cell Proliferation; D018932:Chemokine CCL2 / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006498:Hepatectomy / Q000379:methods*; D022781:Hepatocytes / Q000378:metabolism; D006706:Homeostasis; D007249:Inflammation; D018664:Interleukin-12 / Q000097:blood; D053759:Interleukin-23 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008055:Lipids / Q000737:chemistry; D008099:Liver / Q000293:injuries* / Q000378:metabolism / Q000473:pathology*; D008115:Liver Regeneration; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics*; D015398:Signal Transduction
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D053759:Interleukin-23; D015850:Interleukin-6; D008055:Lipids; D016328:NF-kappa B; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D018664:Interleukin-12; D000410:Alanine Transaminase; D048049:Extracellular Signal-Regulated MAP Kinases