An abundant biliary fatty acid metabolite derived from dietary omega-3 polyunsaturated fatty acids regulates triglycerides
An abundant biliary fatty acid metabolite derived from dietary omega-3 polyunsaturated fatty acids regulates triglycerides
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.
Grevengoed, Trisha J.
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Trammell, Samuel A.J.
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Svenningsen, Jens S.
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Makarov, Mikhail V.
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Nielsen, Thomas Svava
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Jacobsen, Jens Christian Brings
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Calder, Philip
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Migaud, Marie E.
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Cravatt, Benjamin F.
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Gillum, Matthew P.
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15 March 2021
Grevengoed, Trisha J.
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Trammell, Samuel A.J.
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Svenningsen, Jens S.
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Makarov, Mikhail V.
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Nielsen, Thomas Svava
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Jacobsen, Jens Christian Brings
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Calder, Philip
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Migaud, Marie E.
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Cravatt, Benjamin F.
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Gillum, Matthew P.
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Grevengoed, Trisha J., Trammell, Samuel A.J., Svenningsen, Jens S., Makarov, Mikhail V., Nielsen, Thomas Svava, Jacobsen, Jens Christian Brings, Calder, Philip, Migaud, Marie E., Cravatt, Benjamin F. and Gillum, Matthew P.
(2021)
An abundant biliary fatty acid metabolite derived from dietary omega-3 polyunsaturated fatty acids regulates triglycerides.
Journal of Clinical Investigation, 131 (6), [e143861].
(doi:10.1172/JCI143861).
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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Accepted/In Press date: 27 January 2021
e-pub ahead of print date: 28 January 2021
Published date: 15 March 2021
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Funding Information:
The authors acknowledge Lucy Browning, Celia Walker, Susan Jebb, and Annette West for their roles in obtaining plasma from human participants given supplemental DHA and EPA. The authors also acknowledge the Core Facility for Integrated Microscopy, Faculty of Health and Medical Sciences, University of Copenhagen for cryo-EM imaging. This study was supported by the Novo Nordisk Foundation Center for Basic Metabolic Research. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent research center at the University of Copenhagen and is partially funded by an unrestricted donation from the Novo Nordisk Foundation (NNF18CC003490). MEM and MVM were supported by the Mitchell Cancer Institute. BFC was supported by NIH grant DA033760.
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© 2021 American Society for Clinical Investigation. All rights reserved.
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Local EPrints ID: 446750
URI: http://eprints.soton.ac.uk/id/eprint/446750
ISSN: 0021-9738
PURE UUID: 33b60a63-53b5-4b63-8534-2eff60d0908f
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Date deposited: 19 Feb 2021 17:33
Last modified: 06 Jun 2024 01:35
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Contributors
Author:
Trisha J. Grevengoed
Author:
Samuel A.J. Trammell
Author:
Jens S. Svenningsen
Author:
Mikhail V. Makarov
Author:
Thomas Svava Nielsen
Author:
Jens Christian Brings Jacobsen
Author:
Marie E. Migaud
Author:
Benjamin F. Cravatt
Author:
Matthew P. Gillum
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