An abundant biliary metabolite derived from dietary omega-3 polyunsaturated fatty acids regulates triglycerides
Trisha J. Grevengoed, … , Benjamin F. Cravatt, Matthew P. Gillum
Trisha J. Grevengoed, … , Benjamin F. Cravatt, Matthew P. Gillum
Published January 28, 2021
Citation Information: J Clin Invest. 2021;131(6):e143861. https://doi.org/10.1172/JCI143861.
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Research Article Endocrinology Gastroenterology

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

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–containing (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, whereas 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 is a negative feedback mediator that limits 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.

Authors

Trisha J. Grevengoed, Samuel A.J. Trammell, Jens S. Svenningsen, Mikhail V. Makarov, Thomas Svava Nielsen, Jens Christian Brings Jacobsen, Jonas T. Treebak, Philip C. Calder, Marie E. Migaud, Benjamin F. Cravatt, Matthew P. Gillum

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Figure 5

Fish oil feeding of FAAH-S268D mice prevents hypertriglyceridemia and hepatic lipid accumulation.

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Fish oil feeding of FAAH-S268D mice prevents hypertriglyceridemia and he...
Plasma (A) and biliary (B) C22:6 NAT after 3 days of a lard-based HFD (45% kcal fat) or a matched diet containing 20% kcal from fish oil (n = 8–11). (C and D) Plasma TAG with gavage of olive oil (lipid absorption; n = 9–13) or after inhibition of lipoprotein lipase alone (VLDL secretion; n = 3–4). (E) BW change over the 6-week diet period (n = 9–14). (F) Total fat and lean mass after 5 weeks of the indicated diets (n = 9–14). (G) Gonadal white adipose tissue (GWAT) weight (n = 9–14). (H–J) Plasma lipid levels (n = 9–14). (K) Liver weight (n = 9–14). (L) Liver TAG levels after 6 weeks on the indicated diets (n = 9–14). (M) Hepatic expression of lipid metabolism genes and markers of inflammation (n = 6). Data are presented as the mean ± SEM. *P < 0.05 compared with FAAH-WT mice, by 2-way ANOVA; #P < 0.05 compared with HFD feeding within the genotype, by 2-way ANOVA.