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ResearchIn-Press PreviewEndocrinologyGastroenterology Free access | 10.1172/JCI143861

An abundant biliary fatty acid metabolite derived from dietary omega-3 polyunsaturated fatty acids regulates triglycerides

Trisha J. Grevengoed,1 Samuel A. J. Trammell,1 Jens S. Svenningsen,1 Mikhail Makarov,2 Thomas Svava Nielsen,1 Jens C. B. Jacobsen,3 Philip C. Calder,4 Marie E. Migaud,2 Benjamin Cravatt,5 and Matthew P. Gillum1

1Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark

2Department of Pharmacology, University of South Alabama, Mobile, United States of America

3Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

4Faculty of Medicine, University of Southampton, Southampton, United Kingdom

5Departments of Cell Biology and Chemistry, The Scripps Research Institute, La Jolla, United States of America

Find articles by Grevengoed, T. in: JCI | PubMed | Google Scholar |

1Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark

2Department of Pharmacology, University of South Alabama, Mobile, United States of America

3Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

4Faculty of Medicine, University of Southampton, Southampton, United Kingdom

5Departments of Cell Biology and Chemistry, The Scripps Research Institute, La Jolla, United States of America

Find articles by Trammell, S. in: JCI | PubMed | Google Scholar |

1Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark

2Department of Pharmacology, University of South Alabama, Mobile, United States of America

3Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

4Faculty of Medicine, University of Southampton, Southampton, United Kingdom

5Departments of Cell Biology and Chemistry, The Scripps Research Institute, La Jolla, United States of America

Find articles by Svenningsen, J. in: JCI | PubMed | Google Scholar |

1Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark

2Department of Pharmacology, University of South Alabama, Mobile, United States of America

3Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

4Faculty of Medicine, University of Southampton, Southampton, United Kingdom

5Departments of Cell Biology and Chemistry, The Scripps Research Institute, La Jolla, United States of America

Find articles by Makarov, M. in: JCI | PubMed | Google Scholar |

1Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark

2Department of Pharmacology, University of South Alabama, Mobile, United States of America

3Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

4Faculty of Medicine, University of Southampton, Southampton, United Kingdom

5Departments of Cell Biology and Chemistry, The Scripps Research Institute, La Jolla, United States of America

Find articles by Nielsen, T. in: JCI | PubMed | Google Scholar |

1Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark

2Department of Pharmacology, University of South Alabama, Mobile, United States of America

3Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

4Faculty of Medicine, University of Southampton, Southampton, United Kingdom

5Departments of Cell Biology and Chemistry, The Scripps Research Institute, La Jolla, United States of America

Find articles by Jacobsen, J. in: JCI | PubMed | Google Scholar

1Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark

2Department of Pharmacology, University of South Alabama, Mobile, United States of America

3Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

4Faculty of Medicine, University of Southampton, Southampton, United Kingdom

5Departments of Cell Biology and Chemistry, The Scripps Research Institute, La Jolla, United States of America

Find articles by Calder, P. in: JCI | PubMed | Google Scholar |

1Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark

2Department of Pharmacology, University of South Alabama, Mobile, United States of America

3Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

4Faculty of Medicine, University of Southampton, Southampton, United Kingdom

5Departments of Cell Biology and Chemistry, The Scripps Research Institute, La Jolla, United States of America

Find articles by Migaud, M. in: JCI | PubMed | Google Scholar |

1Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark

2Department of Pharmacology, University of South Alabama, Mobile, United States of America

3Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

4Faculty of Medicine, University of Southampton, Southampton, United Kingdom

5Departments of Cell Biology and Chemistry, The Scripps Research Institute, La Jolla, United States of America

Find articles by Cravatt, B. in: JCI | PubMed | Google Scholar

1Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark

2Department of Pharmacology, University of South Alabama, Mobile, United States of America

3Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

4Faculty of Medicine, University of Southampton, Southampton, United Kingdom

5Departments of Cell Biology and Chemistry, The Scripps Research Institute, La Jolla, United States of America

Find articles by Gillum, M. in: JCI | PubMed | Google Scholar

Published January 28, 2021 - More info

J Clin Invest. https://doi.org/10.1172/JCI143861.
Copyright © 2021, American Society for Clinical Investigation
Published January 28, 2021 - Version history
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Abstract

Omega-3 fatty acids from fish oil reduce triglyceride levels in mammals, yet the mechanisms underlying this effect have not been fully clarified despite the clinical use of omega-3 ethyl esters to treat severe hypertriglyceridemia and reduce cardiovascular disease risk in humans. Here we identified in bile a class of hypotriglyceridemic omega-3 fatty acid-derived N-acyl taurines (NATs) that, after dietary omega-3 fatty acid supplementation, increased to concentrations similar to those of steroidal bile acids. The biliary docosahexaenoic acid (DHA) containing NAT, C22:6 NAT, was increased in human and mouse plasma after dietary omega-3 fatty acid supplementation and potently inhibited intestinal triacylglycerol hydrolysis and lipid absorption. Supporting this observation, genetic elevation of endogenous NAT levels in mice impaired lipid absorption, while selective augmentation of C22:6 NAT levels protected against hypertriglyceridemia and fatty liver. When administered pharmacologically, C22:6 NAT accumulated in bile and reduced high fat diet-induced, but not sucrose-induced, hepatic lipid accumulation in mice, suggesting that C22:6 NAT was a negative feedback mediator that limited excess intestinal lipid absorption. Thus, biliary omega-3 NATs may contribute to the hypotriglyceridemic mechanism of action of fish oil and could influence the design of more potent omega-3 fatty acid-based therapeutics.

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