The University of Southampton
University of Southampton Institutional Repository

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.
9ec61aeb-02e2-417d-8215-9c688903f298
Trammell, Samuel A.J.
adfe4ff4-9a76-472f-8923-58fd9bafdaa9
Svenningsen, Jens S.
4b43b815-633b-4ce8-88f1-33914da4070c
Makarov, Mikhail V.
8691ba5a-93fe-41ec-aede-e42cf34b8f70
Nielsen, Thomas Svava
8b67e20a-3ea6-4b18-b8c6-7d34e2130165
Jacobsen, Jens Christian Brings
1bdf5c48-0b86-4ac2-a598-56188153f802
Calder, Philip
1797e54f-378e-4dcb-80a4-3e30018f07a6
Migaud, Marie E.
75262ff3-c2ef-412c-b311-ed5f49f3ce20
Cravatt, Benjamin F.
f9ed149c-710a-44c2-9096-48c0fedcefe7
Gillum, Matthew P.
c037c396-e66a-4fa8-a922-5d565871644e
Grevengoed, Trisha J.
9ec61aeb-02e2-417d-8215-9c688903f298
Trammell, Samuel A.J.
adfe4ff4-9a76-472f-8923-58fd9bafdaa9
Svenningsen, Jens S.
4b43b815-633b-4ce8-88f1-33914da4070c
Makarov, Mikhail V.
8691ba5a-93fe-41ec-aede-e42cf34b8f70
Nielsen, Thomas Svava
8b67e20a-3ea6-4b18-b8c6-7d34e2130165
Jacobsen, Jens Christian Brings
1bdf5c48-0b86-4ac2-a598-56188153f802
Calder, Philip
1797e54f-378e-4dcb-80a4-3e30018f07a6
Migaud, Marie E.
75262ff3-c2ef-412c-b311-ed5f49f3ce20
Cravatt, Benjamin F.
f9ed149c-710a-44c2-9096-48c0fedcefe7
Gillum, Matthew P.
c037c396-e66a-4fa8-a922-5d565871644e

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.

Text
143861-JCI-RG-RV-3_mstext_477792 - Accepted Manuscript
Restricted to Repository staff only
Available under License Creative Commons Attribution.
Request a copy

More information

Accepted/In Press date: 27 January 2021
e-pub ahead of print date: 28 January 2021
Published date: 15 March 2021
Additional Information: 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. Publisher Copyright: © 2021 American Society for Clinical Investigation. All rights reserved.

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

Catalogue record

Date deposited: 19 Feb 2021 17:33
Last modified: 06 Jun 2024 01:35

Export record

Altmetrics

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

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×