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Trimethylamine N-Oxide Binds and Activates PERK to Promote Metabolic Dysfunction.
Cell Metabolism ( IF 27.7 ) Pub Date : 2019-09-19 , DOI: 10.1016/j.cmet.2019.08.021 Sifan Chen 1 , Ayana Henderson 2 , Michael C Petriello 3 , Kymberleigh A Romano 4 , Mary Gearing 2 , Ji Miao 2 , Mareike Schell 5 , Walter J Sandoval-Espinola 6 , Jiahui Tao 7 , Bingdong Sha 7 , Mark Graham 8 , Rosanne Crooke 8 , Andre Kleinridders 5 , Emily P Balskus 6 , Federico E Rey 4 , Andrew J Morris 3 , Sudha B Biddinger 2
Cell Metabolism ( IF 27.7 ) Pub Date : 2019-09-19 , DOI: 10.1016/j.cmet.2019.08.021 Sifan Chen 1 , Ayana Henderson 2 , Michael C Petriello 3 , Kymberleigh A Romano 4 , Mary Gearing 2 , Ji Miao 2 , Mareike Schell 5 , Walter J Sandoval-Espinola 6 , Jiahui Tao 7 , Bingdong Sha 7 , Mark Graham 8 , Rosanne Crooke 8 , Andre Kleinridders 5 , Emily P Balskus 6 , Federico E Rey 4 , Andrew J Morris 3 , Sudha B Biddinger 2
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The gut-microbe-derived metabolite trimethylamine N-oxide (TMAO) is increased by insulin resistance and associated with several sequelae of metabolic syndrome in humans, including cardiovascular, renal, and neurodegenerative disease. The mechanism by which TMAO promotes disease is unclear. We now reveal the endoplasmic reticulum stress kinase PERK (EIF2AK3) as a receptor for TMAO: TMAO binds to PERK at physiologically relevant concentrations; selectively activates the PERK branch of the unfolded protein response; and induces the transcription factor FoxO1, a key driver of metabolic disease, in a PERK-dependent manner. Furthermore, interventions to reduce TMAO, either by manipulation of the gut microbiota or by inhibition of the TMAO synthesizing enzyme, flavin-containing monooxygenase 3, can reduce PERK activation and FoxO1 levels in the liver. Taken together, these data suggest TMAO and PERK may be central to the pathogenesis of the metabolic syndrome.
中文翻译：
三甲胺N-氧化物结合并激活PERK，从而促进代谢功能障碍。
肠道微生物衍生的代谢物三甲胺N-氧化物（TMAO）通过胰岛素抵抗而增加，并与人类代谢综合征的后遗症相关，包括心血管，肾脏和神经退行性疾病。TMAO促进疾病的机制尚不清楚。现在我们揭示内质网应激激酶PERK（EIF2AK3）作为TMAO的受体：TMAO在生理相关浓度下结合PERK；选择性激活未折叠蛋白反应的PERK分支；并以PERK依赖的方式诱导转录因子FoxO1（代谢疾病的关键驱动因素）。此外，通过操纵肠道菌群或抑制TMAO合成酶（含黄素的单加氧酶3）来减少TMAO的干预措施，可以降低肝脏中PERK的活化和FoxO1的水平。
更新日期：2019-11-09
中文翻译：
三甲胺N-氧化物结合并激活PERK，从而促进代谢功能障碍。
肠道微生物衍生的代谢物三甲胺N-氧化物（TMAO）通过胰岛素抵抗而增加，并与人类代谢综合征的后遗症相关，包括心血管，肾脏和神经退行性疾病。TMAO促进疾病的机制尚不清楚。现在我们揭示内质网应激激酶PERK（EIF2AK3）作为TMAO的受体：TMAO在生理相关浓度下结合PERK；选择性激活未折叠蛋白反应的PERK分支；并以PERK依赖的方式诱导转录因子FoxO1（代谢疾病的关键驱动因素）。此外，通过操纵肠道菌群或抑制TMAO合成酶（含黄素的单加氧酶3）来减少TMAO的干预措施，可以降低肝脏中PERK的活化和FoxO1的水平。
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