Fatty acid synthesis suppresses dietary polyunsaturated fatty acid use

• Published in: Nature communications Vol. 15; no. 1; p. 45
• Main Authors: Worthmann, Anna, Ridder, Julius, Piel, Sharlaine Y. L., Evangelakos, Ioannis, Musfeldt, Melina, Voß, Hannah, O’Farrell, Marie, Fischer, Alexander W., Adak, Sangeeta, Sundd, Monica, Siffeti, Hasibullah, Haumann, Friederike, Kloth, Katja, Bierhals, Tatjana, Heine, Markus, Pertzborn, Paul, Pauly, Mira, Scholz, Julia-Josefine, Kundu, Suman, Fuh, Marceline M., Neu, Axel, Tödter, Klaus, Hempel, Maja, Knippschild, Uwe, Semenkovich, Clay F., Schlüter, Hartmut, Heeren, Joerg, Scheja, Ludger, Kubisch, Christian, Schlein, Christian
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.01.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/109; 13/44; 13/89; 38/109; 38/22; 38/23; 38/88; 38/89; 49/90; 631/208/2489/144; 64/60; 692/163/2743; 692/4020/4021/1607/2750; 82/80; Animals; Anti-inflammatory agents; Complex lipids; Diacylglycerol O-acyltransferase; Diet, High-Fat - adverse effects; Diglycerides; Fatty Acids; Fatty Acids, Omega-3 - metabolism; Fatty Acids, Omega-3 - pharmacology; Fatty Acids, Unsaturated; Fatty-acid synthase; High fat diet; Humanities and Social Sciences; Humans; Inflammation; Lipid metabolism; Lipids; Lipogenesis; Lysophosphatidylcholine; Metabolic Diseases; Metabolic disorders; Mice; multidisciplinary; Polyunsaturated fatty acids; Science; Science (multidisciplinary); Supplements; Synthesis; Triglycerides; Triglycerides - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-44364-y

Dietary polyunsaturated fatty acids (PUFA) are increasingly recognized for their health benefits, whereas a high production of endogenous fatty acids – a process called de novo lipogenesis (DNL) - is closely linked to metabolic diseases. Determinants of PUFA incorporation into complex lipids are insufficiently understood and may influence the onset and progression of metabolic diseases. Here we show that fatty acid synthase (FASN), the key enzyme of DNL, critically determines the use of dietary PUFA in mice and humans. Moreover, the combination of FASN inhibition and PUFA-supplementation decreases liver triacylglycerols (TAG) in mice fed with high-fat diet. Mechanistically, FASN inhibition causes higher PUFA uptake via the lysophosphatidylcholine transporter MFSD2A, and a diacylglycerol O-acyltransferase 2 (DGAT2)-dependent incorporation of PUFA into TAG. Overall, the outcome of PUFA supplementation may depend on the degree of endogenous DNL and combining PUFA supplementation and FASN inhibition might be a promising approach to target metabolic disease. Polyunsaturated Fatty Acids (PUFA), such as omega-3 fatty acids, are recognized for their lipid lowering and anti-inflammatory properties. Here, the authors show that endogenous lipid synthesis controls the use of PUFA and thus determine the therapeutic benefit of omega-3 fatty acid supplementation.