Hepatocyte DACH1 Is Increased in Obesity via Nuclear Exclusion of HDAC4 and Promotes Hepatic Insulin Resistance

Autor(es)

Ozcan, Lale ^[1] ; Ghorpade, Devram S. ^[1] ; Zheng, Ze ^[1] ; de Souza, Jane Cristina ^[1] ; Chen, Ke ^[2] ; Bessler, Marc ^[3] ; Bagloo, Melissa ^[3] ; Schrope, Beth ^[3] ; Pestell, Richard ^[2] ; Tabas, Ira ^{[1, 4, 5]}

Afiliação do(s) autor(es)

^[1] Columbia Univ, Dept Med, New York, NY 10032 - USA

^[2] Thomas Jefferson Univ, Dept Canc Biol, Sidney Kimmel Canc Ctr, Philadelphia, PA 19107 - USA

^[3] Columbia Univ, Dept Surg, New York, NY 10032 - USA

^[4] Columbia Univ, Dept Physiol & Cellular Biophys, New York, NY 10032 - USA

^[5] Columbia Univ, Dept Pathol & Cell Biol, New York, NY 10032 - USA

• Tipo de documento: Artigo Científico
• Fonte: CELL REPORTS; v. 15, n. 10, p. 2214-2225, JUN 7 2016.
• Citações Web of Science: 15

Resumo

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 core-pression in hepatocytes emerges as an important link between obesity and insulin resistance. (AU)

• Processo FAPESP: 12/21290-4 - Metabolismo de colesterol e secreção de insulina em ilhotas de camundongos hipercolesterolêmicos: possível participação do estresse de retículo
• Beneficiário: Jane Cristina de Souza Sporkens
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado