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

Sifan Chen; Ayana Henderson; Michael C. Petriello; Kymberleigh A. Romano; Mary Gearing; Ji Miao; Mareike Schell; Walter J. Sandoval-Espinola; Jiahui Tao; Bingdong Sha; Mark Graham; Rosanne Crooke; Andre Kleinridders; Emily P. Balskus; Federico E. Rey; Andrew J. Morris; Sudha B. Biddinger

doi:10.1016/j.cmet.2019.08.021

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

Sifan Chen
, Ayana Henderson
, Michael C. Petriello
, Kymberleigh A. Romano
, Mary Gearing
, Ji Miao
, Mareike Schell
, Walter J. Sandoval-Espinola
, Jiahui Tao
, Bingdong Sha
, Mark Graham
, Rosanne Crooke
, Andre Kleinridders
, Emily P. Balskus
, Federico E. Rey
, Andrew J. Morris
, Sudha B. Biddinger

Internal Medicine

Producción científica: Article › revisión exhaustiva

385 Citas (Scopus)

Resumen

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.

Idioma original	English
Páginas (desde-hasta)	1141-1151.e5
Publicación	Cell Metabolism
Volumen	30
N.º	6
DOI	https://doi.org/10.1016/j.cmet.2019.08.021
Estado	Published - dic 3 2019

Nota bibliográfica

Publisher Copyright:
© 2019

Financiación

These studies were supported by R01HL109650 (S.B.B.), the American Heart Association (Established Investigator Award to S.B.B.), and R00DK100539 (J.M.). M.S. and A.K. were supported by a grant from the German Ministry of Education and Research (BMBF) and the State of Brandenburg ( DZD grant 82DZD00302 ).

Financiadores	Número del financiador
State of Brandenburg	82DZD00302
U.S. Department of Veterans Affairs	I01CX001550
U.S. Department of Veterans Affairs
American the American Heart Association	R00DK100539
American the American Heart Association
Bundesministerium für Bildung und Forschung

ODS de las Naciones Unidas

Este resultado contribuye a los siguientes Objetivos de Desarrollo Sostenible

Good health and well being

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

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10.1016/j.cmet.2019.08.021

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Chen, S., Henderson, A., Petriello, M. C., Romano, K. A., Gearing, M., Miao, J., Schell, M., Sandoval-Espinola, W. J., Tao, J., Sha, B., Graham, M., Crooke, R., Kleinridders, A., Balskus, E. P., Rey, F. E., Morris, A. J., & Biddinger, S. B. (2019). Trimethylamine N-Oxide Binds and Activates PERK to Promote Metabolic Dysfunction. Cell Metabolism, 30(6), 1141-1151.e5. https://doi.org/10.1016/j.cmet.2019.08.021

@article{e67e860010d84752831bf6535f933b3d,

title = "Trimethylamine N-Oxide Binds and Activates PERK to Promote Metabolic Dysfunction",

abstract = "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.",

keywords = "EIF2AK3, FoxO1, PERK, diabetes, endoplasmic reticulum stress, insulin signaling, metabolomics, trimethylamine N-oxide",

author = "Sifan Chen and Ayana Henderson and Petriello, \{Michael C.\} and Romano, \{Kymberleigh A.\} and Mary Gearing and Ji Miao and Mareike Schell and Sandoval-Espinola, \{Walter J.\} and Jiahui Tao and Bingdong Sha and Mark Graham and Rosanne Crooke and Andre Kleinridders and Balskus, \{Emily P.\} and Rey, \{Federico E.\} and Morris, \{Andrew J.\} and Biddinger, \{Sudha B.\}",

note = "Publisher Copyright: {\textcopyright} 2019",

year = "2019",

month = dec,

day = "3",

doi = "10.1016/j.cmet.2019.08.021",

language = "English",

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Chen, S, Henderson, A, Petriello, MC, Romano, KA, Gearing, M, Miao, J, Schell, M, Sandoval-Espinola, WJ, Tao, J, Sha, B, Graham, M, Crooke, R, Kleinridders, A, Balskus, EP, Rey, FE, Morris, AJ & Biddinger, SB 2019, 'Trimethylamine N-Oxide Binds and Activates PERK to Promote Metabolic Dysfunction', Cell Metabolism, vol. 30, n.º 6, pp. 1141-1151.e5. https://doi.org/10.1016/j.cmet.2019.08.021

TY - JOUR

T1 - Trimethylamine N-Oxide Binds and Activates PERK to Promote Metabolic Dysfunction

AU - Chen, Sifan

AU - Henderson, Ayana

AU - Petriello, Michael C.

AU - Romano, Kymberleigh A.

AU - Gearing, Mary

AU - Miao, Ji

AU - Schell, Mareike

AU - Sandoval-Espinola, Walter J.

AU - Tao, Jiahui

AU - Sha, Bingdong

AU - Graham, Mark

AU - Crooke, Rosanne

AU - Kleinridders, Andre

AU - Balskus, Emily P.

AU - Rey, Federico E.

AU - Morris, Andrew J.

AU - Biddinger, Sudha B.

PY - 2019/12/3

Y1 - 2019/12/3

N2 - 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.

AB - 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.

KW - EIF2AK3

KW - FoxO1

KW - PERK

KW - diabetes

KW - endoplasmic reticulum stress

KW - insulin signaling

KW - metabolomics

KW - trimethylamine N-oxide

UR - https://www.scopus.com/pages/publications/85075446550

UR - https://www.scopus.com/pages/publications/85075446550#tab=citedBy

U2 - 10.1016/j.cmet.2019.08.021

DO - 10.1016/j.cmet.2019.08.021

M3 - Article

C2 - 31543404

AN - SCOPUS:85075446550

SN - 1550-4131

VL - 30

SP - 1141-1151.e5

JO - Cell Metabolism

JF - Cell Metabolism

IS - 6

ER -

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

Resumen

Nota bibliográfica

Financiación

ODS de las Naciones Unidas

ASJC Scopus subject areas

Acceder al documento

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