Cited by 427Endoplasmic Reticulum Stress and DiseaseGut microbiota and healthPer- and polyfluoroalkyl substances research

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

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Chen, Sifan, Henderson, Ayana, Petriello, Michael C., Romano, Kymberleigh A., Gearing, Mary, Miao, Ji, Schell, Mareike, Sandoval-Espinola, Walter J., Tao, Jiahui, Sha, Bingdong, Graham, Mark, Crooke, Rosanne, Kleinridders, Andre, Balskus, Emily P., Rey, Federico E., Morris, Andrew J., Biddinger, Sudha B.·2019·Cell Metabolism

DOI 10.1016/j.cmet.2019.08.021

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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.

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Authors: 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.
Affiliations: Boston Children's Hospital (US)
University of Kentucky (US)
University of Wisconsin–Madison (US)
German Center for Diabetes Research (DE)
University of Alabama at Birmingham (US)
Ionis Pharmaceuticals (United States) (US)
Harvard University (US)
Corresponding author: Biddinger, Sudha B.
ORCID: Chen, Sifan
Henderson, Ayana
Petriello, Michael C.
Miao, Ji
Schell, Mareike
Tao, Jiahui
Sha, Bingdong
Balskus, Emily P.
Rey, Federico E.
Morris, Andrew J.
Biddinger, Sudha B.
Venue: Cell Metabolism
Publisher: Elsevier BV
Published: 2019-12
Volume: 30
Issue: 6
Pages: 1141-1151.e5
ISSN: 1550-4131 (ISSN-L)
DOI: 10.1016/j.cmet.2019.08.021
OpenAlex: W2973552995
Cited by: 427
References: 88
Citations by year: 2026: 60 · 2025: 84 · 2024: 63 · 2023: 69 · 2022: 60 · 2021: 50 · 2020: 36 · 2019: 2
FWCI: 19.49
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 368 d)
Locations: Cell Metabolism (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health
Bundesministerium für Bildung und Forschung
American Heart Association (R01HL109650)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
Physical Sciences › Environmental Science › Environmental Chemistry › Per- and polyfluoroalkyl substances research
Keywords: trimethylamine N-oxide, PERK, unfolded protein response, endoplasmic reticulum stress, FOXO1, gut microbiota, FMO3, metabolic syndrome, insulin resistance, liver
MeSH terms: Gastrointestinal Microbiome, Animals, Humans, Indoles, Insulin Resistance, Methylamines, Mice, Inbred C57BL, Mice, Obese, Oxygenases, Mice, Knockout, eIF-2 Kinase, Metabolic Syndrome, Mice, Hep G2 Cells, HEK293 Cells

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

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