SUMMARY 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 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 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.

Completion of intraoperative cholangiography is an important aspect of cholecystectomy in order to identify choledocholithiasis and verify anatomy. With the advent of single-access laparoscopy, standard operative principles should not be compromised. Cholangiography may provide a safer approach to cholecystectomy when adopting a new technique. We present our technique of single-incision cholecystectomy and routine cholangiography with a 95% success rate. The ability to perform single-incision intraoperative cholangiograms will allow a safe, more minimally invasive approach to cholecystectomy with suspected choledocholithiasis and obviate the need to convert to standard multiport laparoscopy for the sole reason of completing cholangiograms.

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