The DOI matches its Crossref record; 86 of the 88 references it cites were found in a registry or an index.
Trimethylamine N-Oxide Binds and Activates PERK to Promote Metabolic Dysfunction
Open accessAbstract
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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“Chen et al. showed that TMAO directly binds to protein kinase R-like endoplasmic reticulum kinase (PERK), a main component of the unfolded protein response – a signaling pathway that adapts the cell to ER stress133 (Figure 1).”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [133]
In the citing paper
“Dietary supplementation of TMAO in C57BL/6J wildtype animals induced hepatic PERK expression, accompanied by increased Fox01, a key transcription factor in insulin singling and impaired glycemic control.”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [133]
In the citing paper
“Genetic manipulation demonstrated that the absence of hepatic PERK blunted the TMAO-induced increases in Fox01 expression and improved glycemic indices.”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [133]
In the citing paper
“Recently, a receptor for TMAO has been reported and shown to participate in TMAO-dependent effects on glucose and insulin metabolism133.”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [133]
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Metadata
- 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
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2019-12
- Volume
- 30
- Issue
- 6
- Pages
- 1141-1151.e5
- ISSN
- 1550-4131 (ISSN-L)
- 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
- 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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