title: Impaired MEK signaling and SERCA expression promote ER stress and apoptosis in insulin-resistant macrophages and are reversed by exenatide treatment.
abstract: Accumulation of toxic lipids evokes the unfolded protein response (UPR) and apoptotic death of macrophages and vascular cells in atherosclerotic plaques. Primary macrophages from insulin-resistant ob/ob and insulin receptor (Insr)(-/-) mice display increased apoptosis in response to loading with free cholesterol or oxysterol, but underlying mechanisms have not been elucidated. We show increased activation of all three major branches of the UPR in response to free cholesterol or oxysterol loading in insulin-resistant macrophages. Inhibition and rescue experiments revealed that defective MEK/extracellular signal\x{2013}related kinase (ERK)/cAMP-responsive element-binding protein (CREBP) signaling in insulin-resistant macrophages leads to decreased expression of sarcoplasmic endoplasmic reticulum (ER) Ca(2+)-ATPase, depletion of ER calcium stores, PKR-like ER kinase activation, and ER stress-associated apoptosis. Activation of macrophage glucagon-like peptide 1 (GLP-1) receptor via the antidiabetic drug exenatide led to improvements in both ERK and AKT signaling and reversed the increase in UPR and apoptosis of insulin-resistant macrophages in atherosclerotic lesions of ob/ob.Ldlr(-/-) and Insr(-/-).Ldlr(-/-) mice. Increased signaling via GLP-1 receptor or the CREBP activator protein kinase A thus offers a way to rescue insulin-resistant macrophages from excessive ER stress responses and apoptosis in insulin resistance and type 2 diabetes.
authors: Department of Medicine, Columbia University, New York, New York, USA. cl534@columbia.edu
authors: Chien-Ping
authors: CP
authors: Liang
authors: Seongah
authors: S
authors: Han
authors: Gang
authors: G
authors: Li
authors: Ira
authors: I
authors: Tabas
authors: Alan R
authors: AR
authors: Tall
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics*; D000077270:Exenatide; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D056811:Unfolded Protein Response / Q000187:drug effects / Q000235:genetics; D014688:Venoms / Q000494:pharmacology*
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D010455:Peptides; D014688:Venoms; D000077270:Exenatide; D020929:Mitogen-Activated Protein Kinase Kinases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases