Positive Health Online

Abstract

WORTHMANN and COLLEAGUES, (1)Department of Biochemistry and Molecular Cell Biology, University Medical      Center Hamburg-Eppendorf, Hamburg, Germany; (2)Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; (3)Section / Core Facility Mass Spectrometry and Proteomics, University Medical  Center Hamburg-Eppendorf, Hamburg, Germany; (4)Sagimet Biosciences Inc., 155 Bovet Rd., San Mateo, CA, 94402, USA; (5)Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Harvard University, Boston, MA, USA;(6)Department of Cell Biology, Harvard Medical School, Boston, MA, USA; (7)Division of Endocrinology, Metabolism & Lipid Research, Department of Medicine, Washington University, St. Louis, MO, USA; (8)National Institute of Immunology, New Delhi, India; (9)Department of Biochemistry, University of Delhi South Campus, New Delhi 110021 and Department of Biological Sciences, Birla Institute of Technology and Science Pilani, K K Birla Goa Campus, Goa, 403726, India; (10)Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; (11)Institute of Human Genetics, University Hospital Heidelberg, Im Neuenheimer Feld 440, 69120, Heidelberg, Germany; (12)Department of General and Visceral Surgery, University Hospital Ulm, Ulm, Germany; (13)Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. c.schlein@uke.de .research how fatty acid synthase (FASN), the key enzyme of DNL, critically  determines the use of dietary PUFA in mice and humans

Background

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.  

Methodology

Determinants of PUFA incorporation into complex lipids are insufficiently   understood and may influence the onset and progression of metabolic diseases.   

Results

The authors 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.

Conclusion

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. © 2024. The Author(s). Conflict of interest statement: M.O. is an employee of Sagimet. C.S. has been an invited speaker for Daiichi Sankyo. All other authors declared no conflicting interests.

References

Worthmann A(1), Ridder J(2), Piel SYL(2), Evangelakos I(2), Musfeldt M(2), Voß    H(3), O'Farrell M(4), Fischer AW(1)(5)(6), Adak S(7), Sundd M(8), Siffeti H(2),    Haumann F(2), Kloth K(2), Bierhals T(2), Heine M(1), Pertzborn P(1), Pauly M(1),    Scholz JJ(2), Kundu S(9), Fuh MM(1), Neu A(10), Tödter K(1), Hempel M(2)(11),    Knippschild U(12), Semenkovich CF(7), Schlüter H(3), Heeren J(1), Scheja L(1), Kubisch C(2), Schlein C(13). Fatty acid synthesis suppresses dietary polyunsaturated fatty acid use. Nat Commun. ;15(1):45.  DOI: 10.1038/s41467-023-44364-y . Jan 2 2024.