Forkhead Transcription Factors (FoxOs) Promote Apoptosis of Insulin-Resistant Macrophages During Cholesterol-Induced Endoplasmic Reticulum Stress

View/ Open
Author
Senokuchi, Takafumi
Liang, Chien-Ping
Seimon, Tracie A.
Han, Seongah
Matsumoto, Michihiro
Accili, Domenico
Tabas, Ira
Tall, Alan R.
Paik, Ji-Hye
Note: Order does not necessarily reflect citation order of authors.
Published Version
https://doi.org/10.2337/db08-0520Metadata
Show full item recordCitation
Senokuchi, Takafumi, Chien-Ping Liang, Tracie A. Seimon, Seongah Han, Michihiro Matsumoto, Alexander S. Banks, Ji-Hye Paik, et al. 2008. Forkhead transcription factors (FoxOs) promote apoptosis of insulin-resistant macrophages during cholesterol-induced endoplasmic reticulum stress. Diabetes 57(11): 2967-2976.Abstract
OBJECTIVE—Endoplasmic reticulum stress increases macrophage apoptosis, contributing to the complications of atherosclerosis. Insulin-resistant macrophages are more susceptible to endoplasmic reticulum stress–associated apoptosis probably contributing to macrophage death and necrotic core formation in atherosclerotic plaques in type 2 diabetes. However, the molecular mechanisms of increased apoptosis in insulin-resistant macrophages remain unclear. RESEARCH DESIGN AND METHODS—The studies were performed in insulin-resistant macrophages isolated from insulin receptor knockout or ob/ob mice. Gain- or loss-of-function approaches were used to evaluate the roles of forkhead transcription factors (FoxOs) in endoplasmic reticulum stress–associated macrophage apoptosis. RESULTS—Insulin-resistant macrophages showed attenuated Akt activation and increased nuclear localization of FoxO1 during endoplasmic reticulum stress induced by free cholesterol loading. Overexpression of active FoxO1 or FoxO3 failed to induce apoptosis in unchallenged macrophages but exacerbated apoptosis in macrophages with an active endoplasmic reticulum stress response. Conversely, macrophages with genetic knockouts of FoxO1, -3, and -4 were resistant to apoptosis in response to endoplasmic reticulum stress. FoxO1 was shown by chromatin immunoprecipitation and promoter expression analysis to induce inhibitor of κBɛ gene expression and thereby to attenuate the increase of nuclear p65 and nuclear factor-κB activity during endoplasmic reticulum stress, with proapoptotic and anti-inflammatory consequences. CONCLUSIONS—Decreased Akt and increased FoxO transcription factor activity during the endoplasmic reticulum stress response leads to increased apoptosis of insulin-resistant macrophages. FoxOs may have a dual cellular function, resulting in either proapoptotic or anti-inflammatory effects in an endoplasmic reticulum stress–modulated manner. In the complex plaque milieu, the ultimate effect is likely to be an increase in macrophage apoptosis, plaque inflammation, and destabilization.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2570393/pdf/Terms of Use
This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAACitable link to this page
http://nrs.harvard.edu/urn-3:HUL.InstRepos:4882674
Collections
- HMS Scholarly Articles [17714]
Contact administrator regarding this item (to report mistakes or request changes)