TY - JOUR
T1 - Hepatocyte DACH1 Is Increased in Obesity via Nuclear Exclusion of HDAC4 and Promotes Hepatic Insulin Resistance
AU - Ozcan, Lale
AU - Ghorpade, Devram S.
AU - Zheng, Ze
AU - de Souza, Jane Cristina
AU - Chen, Ke
AU - Bessler, Marc
AU - Bagloo, Melissa
AU - Schrope, Beth
AU - Pestell, Richard
AU - Tabas, Ira
N1 - Funding Information:
We thank Dr. Harold A. Singer (Albany Medical College) for adeno-LacZ and K43A-CaMKII, Dr. Marc Montminy (Salk Institute for Biological Studies) for adeno-sh-ATF6 and -ATF6-N, Dr. Eric Olson (UT Southwestern) for adeno-HDAC4S3A, Dr. Reuben Shaw (Salk Institute for Biological Studies) for adeno-sh-HDAC4, Dr. Tso-Pang Yao (Duke University) for anti-pSer-465-HDAC4 antibody, and Dr. Matthew Molusky (Columbia University) for help with ChIP experiments. This work was supported in part by awards from the American Heart Association (11SDG5300022) and NYONRC (DK26687) to L.O., Sao Paulo Research Foundation (FAPESP/BEPE 2012/21290-4) to J.C.d.S., NIH grants (R01CA70896, R01CA75503, and R01CA86072), the Breast Cancer Research Foundation to R.P., and NIH grants (HL087123 and HL075662) and a Harrington Scholar-Innovator Award from the Harrington Discovery Institute to I.T. Work conducted at the Sidney Kimmel Cancer Center was supported by the NIH Cancer Center Core grant (P30CA56036) to R.P. This project was also supported in part from the Dr. Ralph and Marian C. Falk Medical Research Trust to R.P. and a grant from the Pennsylvania Department of Health to R.P. This work was supported by an American Heart Association Scientist Development Grant (11SDG5300022) and a NYONRC Pilot and Feasibility Grant (DK26687) to L.O., a São Paulo Research Foundation grant (FAPESP/BEPE 2012/21290-4) to J.C.d.S., and NIH grants CA132115-05A1 to R.P. and HL087123 and HL075662 to I.T. L.O. and I.T. are in the group of cofounders of Tabomedex Biosciences, which is developing inhibitors of the upstream kinases in the pathway described in this report for the treatment of T2D. The actual drug target itself is not part of the current study.
Publisher Copyright:
© 2016 The Author(s).
PY - 2016/6/7
Y1 - 2016/6/7
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/84969980373
U2 - 10.1016/j.celrep.2016.05.006
DO - 10.1016/j.celrep.2016.05.006
M3 - Article
C2 - 27239042
AN - SCOPUS:84969980373
SN - 2211-1247
VL - 15
SP - 2214
EP - 2225
JO - Cell Reports
JF - Cell Reports
IS - 10
ER -
SDG 3 Good Health and Well-being