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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
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.
0021-9738
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.
9ec61aeb-02e2-417d-8215-9c688903f298
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).

Record type: Article

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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143861-JCI-RG-RV-3_mstext_477792 - Accepted Manuscript
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Accepted/In Press date: 27 January 2021
e-pub ahead of print date: 28 January 2021

Identifiers

Local EPrints ID: 446750
URI: http://eprints.soton.ac.uk/id/eprint/446750
ISSN: 0021-9738
PURE UUID: 33b60a63-53b5-4b63-8534-2eff60d0908f
ORCID for Philip Calder: ORCID iD orcid.org/0000-0002-6038-710X

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Date deposited: 19 Feb 2021 17:33
Last modified: 22 Nov 2021 02:39

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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: Philip Calder ORCID iD
Author: Marie E. Migaud
Author: Benjamin F. Cravatt
Author: Matthew P. Gillum

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