Fatty acid synthesis suppresses dietary polyunsaturated fatty acid use

Anna Worthmann; Julius Ridder; Sharlaine Y.L. Piel; Ioannis Evangelakos; Melina Musfeldt; Hannah Voß; Marie O’Farrell; Alexander W. Fischer; Sangeeta Adak; Monica Sundd; Hasibullah Siffeti; Friederike Haumann; Katja Kloth; Tatjana Bierhals; Markus Heine; Paul Pertzborn; Mira Pauly; Julia Josefine Scholz; Suman Kundu; Marceline M. Fuh; Axel Neu; Klaus Tödter; Maja Hempel; Uwe Knippschild; Clay F. Semenkovich; Hartmut Schlüter; Joerg Heeren; Ludger Scheja; Christian Kubisch; Christian Schlein

doi:10.1038/s41467-023-44364-y

Fatty acid synthesis suppresses dietary polyunsaturated fatty acid use

Anna Worthmann, Julius Ridder, Sharlaine Y.L. Piel, Ioannis Evangelakos, Melina Musfeldt, Hannah Voß, Marie O’Farrell, Alexander W. Fischer, Sangeeta Adak, Monica Sundd, Hasibullah Siffeti, Friederike Haumann, Katja Kloth, Tatjana Bierhals, Markus Heine, Paul Pertzborn, Mira Pauly, Julia Josefine Scholz, Suman Kundu, Marceline M. FuhAxel Neu, Klaus Tödter, Maja Hempel, Uwe Knippschild, Clay F. Semenkovich, Hartmut Schlüter, Joerg Heeren, Ludger Scheja, Christian Kubisch, Christian Schlein

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Abstract

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.

Original language	English
Article number	45
Journal	Nature communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-44364-y
State	Published - Dec 2024

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Worthmann, A., Ridder, J., Piel, S. Y. L., Evangelakos, I., Musfeldt, M., Voß, H., O’Farrell, M., Fischer, A. W., Adak, S., Sundd, M., Siffeti, H., Haumann, F., Kloth, K., Bierhals, T., Heine, M., Pertzborn, P., Pauly, M., Scholz, J. J., Kundu, S., ... Schlein, C. (2024). Fatty acid synthesis suppresses dietary polyunsaturated fatty acid use. Nature communications, 15(1), Article 45. https://doi.org/10.1038/s41467-023-44364-y

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title = "Fatty acid synthesis suppresses dietary polyunsaturated fatty acid use",

abstract = "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.",

author = "Anna Worthmann and Julius Ridder and Piel, {Sharlaine Y.L.} and Ioannis Evangelakos and Melina Musfeldt and Hannah Vo{\ss} and Marie O{\textquoteright}Farrell and Fischer, {Alexander W.} and Sangeeta Adak and Monica Sundd and Hasibullah Siffeti and Friederike Haumann and Katja Kloth and Tatjana Bierhals and Markus Heine and Paul Pertzborn and Mira Pauly and Scholz, {Julia Josefine} and Suman Kundu and Fuh, {Marceline M.} and Axel Neu and Klaus T{\"o}dter and Maja Hempel and Uwe Knippschild and Semenkovich, {Clay F.} and Hartmut Schl{\"u}ter and Joerg Heeren and Ludger Scheja and Christian Kubisch and Christian Schlein",

note = "Publisher Copyright: {\textcopyright} 2024, The Author(s).",

year = "2024",

month = dec,

doi = "10.1038/s41467-023-44364-y",

language = "English",

volume = "15",

journal = "Nature communications",

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Worthmann, A, Ridder, J, Piel, SYL, Evangelakos, I, Musfeldt, M, Voß, H, O’Farrell, M, Fischer, AW, Adak, S, Sundd, M, Siffeti, H, Haumann, F, Kloth, K, Bierhals, T, Heine, M, Pertzborn, P, Pauly, M, Scholz, JJ, Kundu, S, Fuh, MM, Neu, A, Tödter, K, Hempel, M, Knippschild, U, Semenkovich, CF, Schlüter, H, Heeren, J, Scheja, L, Kubisch, C & Schlein, C 2024, 'Fatty acid synthesis suppresses dietary polyunsaturated fatty acid use', Nature communications, vol. 15, no. 1, 45. https://doi.org/10.1038/s41467-023-44364-y

TY - JOUR

T1 - Fatty acid synthesis suppresses dietary polyunsaturated fatty acid use

AU - Worthmann, Anna

AU - Ridder, Julius

AU - Piel, Sharlaine Y.L.

AU - Evangelakos, Ioannis

AU - Musfeldt, Melina

AU - Voß, Hannah

AU - O’Farrell, Marie

AU - Fischer, Alexander W.

AU - Adak, Sangeeta

AU - Sundd, Monica

AU - Siffeti, Hasibullah

AU - Haumann, Friederike

AU - Kloth, Katja

AU - Bierhals, Tatjana

AU - Heine, Markus

AU - Pertzborn, Paul

AU - Pauly, Mira

AU - Scholz, Julia Josefine

AU - Kundu, Suman

AU - Fuh, Marceline M.

AU - Neu, Axel

AU - Tödter, Klaus

AU - Hempel, Maja

AU - Knippschild, Uwe

AU - Semenkovich, Clay F.

AU - Schlüter, Hartmut

AU - Heeren, Joerg

AU - Scheja, Ludger

AU - Kubisch, Christian

AU - Schlein, Christian

PY - 2024/12

Y1 - 2024/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85181254659&partnerID=8YFLogxK

U2 - 10.1038/s41467-023-44364-y

DO - 10.1038/s41467-023-44364-y

M3 - Article

C2 - 38167725

AN - SCOPUS:85181254659

SN - 2041-1723

VL - 15

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 45

ER -

Fatty acid synthesis suppresses dietary polyunsaturated fatty acid use

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