title: β-Arrestin 2 Promotes Hepatocyte Apoptosis by Inhibiting Akt Protein.
abstract: Recent studies reveal that multifunctional protein β-arrestin 2 (Arrb2) modulates cell apoptosis. Survival and various aspects of liver injury were investigated in WT and Arrb2 KO mice after bile duct ligation (BDL). We found that deficiency of Arrb2 enhances survival and attenuates hepatic injury and fibrosis. Following BDL, Arrb2-deficient mice as compared with WT controls displayed a significant reduction of hepatocyte apoptosis as demonstrated by the TUNEL assay. Following BDL, the levels of phospho-Akt and phospho-glycogen synthase kinase 3β (GSK3β) in the livers were significantly increased in Arrb2 KO compared with WT mice, although p-p38 increased in WT but not in Arrb2-deficient mice. Inhibition of GSK3β following BDL decreases hepatic apoptosis and decreased p-p38 in WT mice but not in Arrb2 KO mice. Activation of Fas receptor with Jo2 reduces phospho-Akt and increases apoptosis in WT cells and WT mice but not in Arrb2-deficient cells and Arrb2-deficient mice. Consistent with direct interaction of Arrb2 with and regulating Akt phosphorylation, the expression of a full-length or N terminus but not the C terminus of Arrb2 reduces Akt phosphorylation and coimmunoprecipates with Akt. These results reveal that the protective effect of deficiency of Arrb2 is due to loss of negative regulation of Akt due to BDL and decreased downstream GSK3β and p38 MAPK signaling pathways.
authors.affiliation: From the Department of Internal Medicine, College of Medicine, East Tennessee State University, Johnson City, Tennessee 37604 and yin@etsu.edu.
authors.forename: Deling
authors.identifier: http://orcid.org/0000-0002-6073-5581
authors.initials: D
authors.lastname: Yin
authors.affiliation: From the Department of Internal Medicine, College of Medicine, East Tennessee State University, Johnson City, Tennessee 37604 and.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Yang
authors.affiliation: From the Department of Internal Medicine, College of Medicine, East Tennessee State University, Johnson City, Tennessee 37604 and.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: the Department of Cardiothoracic Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Huimin
authors.initials: H
authors.lastname: Fan
authors.affiliation: From the Department of Internal Medicine, College of Medicine, East Tennessee State University, Johnson City, Tennessee 37604 and.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: From the Department of Internal Medicine, College of Medicine, East Tennessee State University, Johnson City, Tennessee 37604 and.
authors.forename: Yimin
authors.initials: Y
authors.lastname: Feng
authors.affiliation: From the Department of Internal Medicine, College of Medicine, East Tennessee State University, Johnson City, Tennessee 37604 and.
authors.forename: Charles
authors.initials: C
authors.lastname: Stuart
authors.affiliation: From the Department of Internal Medicine, College of Medicine, East Tennessee State University, Johnson City, Tennessee 37604 and.
authors.forename: Dan
authors.initials: D
authors.lastname: Hu
authors.affiliation: From the Department of Internal Medicine, College of Medicine, East Tennessee State University, Johnson City, Tennessee 37604 and.
authors.forename: Yi
authors.initials: Y
authors.lastname: Caudle
authors.affiliation: From the Department of Internal Medicine, College of Medicine, East Tennessee State University, Johnson City, Tennessee 37604 and.
authors.forename: Nanchang
authors.initials: N
authors.lastname: Xie
authors.affiliation: the Department of Cardiothoracic Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Zhongmin
authors.initials: Z
authors.lastname: Liu
authors.affiliation: From the Department of Internal Medicine, College of Medicine, East Tennessee State University, Johnson City, Tennessee 37604 and gene_lesage@yahoo.com.
authors.forename: Gene
authors.initials: G
authors.lastname: LeSage
mesh_terms: D000818:Animals; D017209:Apoptosis; D019390:Arrestins / Q000172:deficiency / Q000378:metabolism*; D001652:Bile Ducts / Q000378:metabolism; D004789:Enzyme Activation; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D022781:Hepatocytes / Q000473:pathology*; D008026:Ligation; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016019:Survival Analysis; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D019014:fas Receptor / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C000605258:Arrb2 protein, mouse; D019390:Arrestins; C491899:Fas protein, mouse; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D019014:fas Receptor; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3
keywords: Akt PKB; BDL; apoptosis; gene regulation; liver injury; signal transduction; β-arrestin 2