Trimethylamine N-Oxide Binds and Activates PERK to Promote Metabolic Dysfunction

被引:268
|
作者
Chen, Sifan [1 ,2 ]
Henderson, Ayana [2 ]
Petriello, Michael C. [3 ,4 ]
Romano, Kymberleigh A. [5 ]
Gearing, Mary [2 ]
Miao, Ji [2 ]
Schell, Mareike [6 ,7 ]
Sandoval-Espinola, Walter J. [8 ]
Tao, Jiahui [9 ]
Sha, Bingdong [9 ]
Graham, Mark [10 ]
Crooke, Rosanne [10 ]
Kleinridders, Andre [6 ,7 ]
Balskus, Emily P. [8 ]
Rey, Federico E. [5 ]
Morris, Andrew J. [3 ,4 ]
Biddinger, Sudha B. [2 ]
机构
[1] Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Med Res Ctr, Guangzhou, Guangdong, Peoples R China
[2] Harvard Med Sch, Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA
[3] Univ Kentucky, Coll Med, Div Cardiovasc Med, Lexington, KY USA
[4] Lexington Vet Affairs Med Ctr, Lexington, KY USA
[5] Univ Wisconsin, Dept Bacteriol, Madison, WI 53706 USA
[6] German Inst Human Nutr, Cent Regulat Metab, D-14558 Nuthetal, Germany
[7] German Ctr Diabet Res, D-85764 Munich, Germany
[8] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA
[9] Univ Alabama Birmingham, Dept Cell Dev & Integrat Biol, Birmingham, AL USA
[10] Ionis Pharmaceut, Carlsbad, CA USA
关键词
ENDOPLASMIC-RETICULUM STRESS; INSULIN-RESISTANCE; ER STRESS; SMALL-MOLECULE; EXPRESSION; GLUCOSE; CELLS; LIVER; MICE; TMAO;
D O I
10.1016/j.cmet.2019.08.021
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:1141 / +
页数:16
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