2016
DOI: 10.1016/j.celrep.2016.05.006
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Hepatocyte DACH1 Is Increased in Obesity via Nuclear Exclusion of HDAC4 and Promotes Hepatic Insulin Resistance

Abstract: 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… Show more

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Cited by 47 publications
(53 citation statements)
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“…We have shown that increased activation of CaMKII in lesional macrophages is associated with advanced and symptomatic atherosclerotic disease in both humans and mice and that deletion of myeloid CaMKIIγ in atheroprone mice suppresses development of these advanced plaque characteristics. When considered together with the possible roles of CaMKII in lesional smooth muscle cells (69,70), overactive hepatocyte CaMKII in obesity-associated insulin resistance and type 2 diabetes (13)(14)(15), and the role of overactive CaMKII in cardiomyocytes in heart failure (12), our findings suggest the potential of targeting this common upstream pathway as an integrated therapeutic approach to cardiometabolic disease.…”
Section: Discussionmentioning
confidence: 99%
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“…We have shown that increased activation of CaMKII in lesional macrophages is associated with advanced and symptomatic atherosclerotic disease in both humans and mice and that deletion of myeloid CaMKIIγ in atheroprone mice suppresses development of these advanced plaque characteristics. When considered together with the possible roles of CaMKII in lesional smooth muscle cells (69,70), overactive hepatocyte CaMKII in obesity-associated insulin resistance and type 2 diabetes (13)(14)(15), and the role of overactive CaMKII in cardiomyocytes in heart failure (12), our findings suggest the potential of targeting this common upstream pathway as an integrated therapeutic approach to cardiometabolic disease.…”
Section: Discussionmentioning
confidence: 99%
“…There are 4 CaMKII isoforms, α, β, δ, and γ, each encoded by a distinct gene. Recent studies from our lab have delineated a central role for overactive CaMKIIγ in hepatocytes in the development of obesity-induced insulin resistance and diabetes (13)(14)(15). Interestingly, the same isoform is expressed by macrophages, and previous in vitro work from our lab suggested that CaMKIIγ could participate in certain types of apoptosis pathways in macrophages (16).…”
Section: Introductionmentioning
confidence: 94%
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