title: Hepatocyte DACH1 Is Increased in Obesity via Nuclear Exclusion of HDAC4 and Promotes Hepatic Insulin Resistance.
abstract: Defective insulin signaling in hepatocytes is a key factor in type 2 diabetes. In obesity, activation of calcium/calmodulin-dependent protein kinase II (CaMKII) in hepatocytes suppresses ATF6, which triggers a PERK-ATF4-TRB3 pathway that disrupts insulin signaling. Elucidating how CaMKII suppresses ATF6 is therefore essential to understanding this insulin resistance pathway. We show that CaMKII phosphorylates and blocks nuclear translocation of histone deacetylase 4 (HDAC4). As a result, HDAC4-mediated SUMOylation of the corepressor DACH1 is decreased, which protects DACH1 from proteasomal degradation. DACH1, together with nuclear receptor corepressor (NCOR), represses Atf6 transcription, leading to activation of the PERK-TRB3 pathway and defective insulin signaling. DACH1 is increased in the livers of obese mice and humans, and treatment of obese mice with liver-targeted constitutively nuclear HDAC4 or DACH1 small hairpin RNA (shRNA) increases ATF6, improves hepatocyte insulin signaling, and protects against hyperglycemia and hyperinsulinemia. Thus, DACH1-mediated corepression in hepatocytes emerges as an important link between obesity and insulin resistance.
authors.affiliation: Department of Medicine, Columbia University, New York, NY 10032, USA. Electronic address: lo2192@columbia.edu.
authors.forename: Lale
authors.initials: L
authors.lastname: Ozcan
authors.affiliation: Department of Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: Devram S
authors.initials: DS
authors.lastname: Ghorpade
authors.affiliation: Department of Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: Ze
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Department of Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: Jane Cristina
authors.initials: JC
authors.lastname: de Souza
authors.affiliation: Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Surgery, Columbia University, New York, NY 10032, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Bessler
authors.affiliation: Department of Surgery, Columbia University, New York, NY 10032, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Bagloo
authors.affiliation: Department of Surgery, Columbia University, New York, NY 10032, USA.
authors.forename: Beth
authors.initials: B
authors.lastname: Schrope
authors.affiliation: Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Pestell
authors.affiliation: Department of Medicine, Columbia University, New York, NY 10032, USA; Department of Physiology and Cellular Biophysics, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA. Electronic address: iat1@columbia.edu.
authors.forename: Ira
authors.initials: I
authors.lastname: Tabas
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D059305:Diet, High-Fat; D005136:Eye Proteins / Q000378:metabolism*; D020868:Gene Silencing; D005947:Glucose / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism*; D006706:Homeostasis; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism* / Q000473:pathology*; D008820:Mice, Obese; D056971:Nuclear Receptor Co-Repressor 1 / Q000378:metabolism; D009765:Obesity / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D021381:Protein Transport; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058207:Sumoylation
chemical_list: D051702:Activating Transcription Factor 6; C497112:Atf6 protein, mouse; C456264:Dach1 protein, mouse; D005136:Eye Proteins; C539128:Ncor1 protein, mouse; D056971:Nuclear Receptor Co-Repressor 1; D012333:RNA, Messenger; D051057:Proto-Oncogene Proteins c-akt; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D046988:Proteasome Endopeptidase Complex; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases; D005947:Glucose