美国波士顿儿童医院Sudha B. Biddinger课题组研究揭示三甲胺N -氧化物结合并激活内质网应激激酶（PERK）促进代谢功能障碍。相关论文2019年9月19日在线发表于《细胞—代谢》杂志。
他们揭示，PERK（EIF2AK3）作为肠道微生物衍生的代谢物三甲胺N-氧化物（TMAO）的受体，TMAO在生理学相关浓度下与PERK结合，选择性地激活应答未折叠蛋白质的PERK分支，并以PERK依赖的方式诱导转录因子FoxO1，它是代谢疾病的关键驱动因子。此外，通过操纵肠道微生物群或通过抑制TMAO合成酶，含黄素的单加氧酶3来减少TMAO的干预可以降低肝脏中的PERK活化和FoxO1水平。总之，这些数据表明TMAO和PERK可能是代谢综合征发病机制的核心。
据悉，TMAO因胰岛素抵抗而增加，并伴随着人类代谢综合征的几种后遗症，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。
附：英文原文
Title: Trimethylamine N-Oxide Binds and Activates PERK to Promote Metabolic Dysfunction
Author: Sifan Chen, Ayana Henderson, Michael Petriello, Kymberleigh A. Romano, Mary Gearing, Ji Miao, Mareike Schell, Walter J. Sandoval-EspinolaEspinola, Jiahui Tao, Bingdong Sha, Mark Graham, Rosanne Crooke, Andre Kleinridders, Emily P. Balskus, Federico E. Rey, Andrew Morris, Sudha B. Biddinger
Issue&Volume: 19 September 2019
Summary:
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.
DOI: 10.1016/j.cmet.2019.08.021
Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30495-4
Cell Metabolism：《细胞—代谢》，创刊于2005年。隶属于细胞出版社，最新IF：31.373
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本期文章：《细胞—代谢》：Online/在线发表
