학술논문
Trimethylamine N-Oxide Binds and Activates PERK to Promote Metabolic Dysfunction.
Document Type
Academic Journal
Author
Chen S; Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China; Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.; Henderson A; Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.; Petriello MC; Division of Cardiovascular Medicine, College of Medicine, University of Kentucky, Lexington, KY, USA; Lexington Veterans Affairs Medical Center, Lexington, KY, USA.; Romano KA; Department of Bacteriology, University of Wisconsin-Madison, Madison, WI, USA.; Gearing M; Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.; Miao J; Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.; Schell M; German Institute of Human Nutrition, Central Regulation of Metabolism, 14558 Nuthetal, Germany; German Center for Diabetes Research, 85764 München-Neuherberg, Germany.; Sandoval-Espinola WJ; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.; Tao J; Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA.; Sha B; Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA.; Graham M; Ionis Pharmaceuticals, Carlsbad, CA, USA.; Crooke R; Ionis Pharmaceuticals, Carlsbad, CA, USA.; Kleinridders A; German Institute of Human Nutrition, Central Regulation of Metabolism, 14558 Nuthetal, Germany; German Center for Diabetes Research, 85764 München-Neuherberg, Germany.; Balskus EP; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.; Rey FE; Department of Bacteriology, University of Wisconsin-Madison, Madison, WI, USA.; Morris AJ; Division of Cardiovascular Medicine, College of Medicine, University of Kentucky, Lexington, KY, USA; Lexington Veterans Affairs Medical Center, Lexington, KY, USA.; Biddinger SB; Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: sudha.biddinger@childrens.harvard.edu.
Source
Publisher: Cell Press Country of Publication: United States NLM ID: 101233170 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1932-7420 (Electronic) Linking ISSN: 15504131 NLM ISO Abbreviation: Cell Metab Subsets: MEDLINE
Subject
Language
English
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.
(Published by Elsevier Inc.)
(Published by Elsevier Inc.)