title: BubR1 Insufficiency Impairs Liver Regeneration in Aged Mice after Hepatectomy through Intercalated Disc Abnormality.
abstract: A delay in liver regeneration after partial hepatectomy (PHx) leads to acute liver injury, and such delays are frequently observed in aged patients. BubR1 (budding uninhibited by benzimidazole-related 1) controls chromosome mitotic segregation through the spindle assembly checkpoint, and BubR1 down-regulation promotes aging-associated phenotypes. In this study we investigated the effects of BubR1 insufficiency on liver regeneration in mice. Low-BubR1-expressing mutant (BubR1(L/L)) mice had a delayed recovery of the liver weight-to-body weight ratio and increased liver deviation enzyme levels after PHx. Microscopic observation of BubR1(L/L) mouse liver showed an increased number of necrotic hepatocytes and intercalated disc anomalies, resulting in widened inter-hepatocyte and perisinusoidal spaces, smaller hepatocytes and early-stage microvilli atrophy. Up-regulation of desmocollin-1 (DSC1) was observed in wild-type, but not BubR1(L/L), mice after PHx. In addition, knockdown of BubR1 expression caused down-regulation of DSC1 in a human keratinocyte cell line. BubR1 insufficiency results in the impaired liver regeneration through weakened microstructural adaptation against PHx, enhanced transient liver failure and delayed hepatocyte proliferation. Thus, our data suggest that a reduction in BubR1 levels causes failure of liver regeneration through the DSC1 abnormality.
authors: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: Ayae
authors: A
authors: Ikawa-Yoshida
authors: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: Takuya
authors: T
authors: Matsumoto
authors: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: Shinji
authors: S
authors: Okano
authors: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: Yukihiko
authors: Y
authors: Aoyagi
authors: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: Yutaka
authors: Y
authors: Matsubara
authors: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: Tadashi
authors: T
authors: Furuyama
authors: Department of Medical Biophysics and Radiation Biology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: Yoshimichi
authors: Y
authors: Nakatsu
authors: Department of Medical Biophysics and Radiation Biology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: Teruhisa
authors: T
authors: Tsuzuki
authors: Division of Pathophysiological and Experimental Pathology, Department of Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: Mitsuho
authors: M
authors: Onimaru
authors: Center for Clinical and Translational Research, Kyushu University, Fukuoka, Japan.
authors: Tomoko
authors: T
authors: Ohkusa
authors: Department of Endocrine and Metabolic Diseases / Diabetes Mellitus Kyushu University, Fukuoka, Japan.
authors: Masatoshi
authors: M
authors: Nomura
authors: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: Yoshihiko
authors: Y
authors: Maehara
mesh_terms: D000367:Age Factors; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D051187:Desmocollins; D006498:Hepatectomy / Q000379:methods*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D008115:Liver Regeneration / Q000235:genetics*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference
chemical_list: C584278:Bub1b protein, mouse; D018797:Cell Cycle Proteins; D051187:Desmocollins; C489910:Dsc1 protein, mouse; D008562:Membrane Glycoproteins; D017346:Protein Serine-Threonine Kinases