Identification of an alternative triglyceride biosynthesis pathway.

Autor: McLelland GL; Oncode Institute, Division of Biochemistry, The Netherlands Cancer Institute, Amsterdam, The Netherlands. g.mclelland@nki.nl., Lopez-Osias M; Oncode Institute, Division of Biochemistry, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Verzijl CRC; Department of Pediatrics, Section of Molecular Metabolism and Nutrition, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands., Ellenbroek BD; Oncode Institute, Division of Biochemistry, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Oliveira RA; Oncode Institute, Division of Biochemistry, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Boon NJ; Oncode Institute, Division of Biochemistry, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Dekker M; Oncode Institute, Division of Biochemistry, The Netherlands Cancer Institute, Amsterdam, The Netherlands., van den Hengel LG; Oncode Institute, Division of Biochemistry, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Ali R; Animal Modeling Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Janssen H; Electron Microscope Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Song JY; Animal Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Krimpenfort P; Animal Modeling Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands., van Zutphen T; Department of Pediatrics, Section of Molecular Metabolism and Nutrition, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.; Faculty Campus Fryslân, University of Groningen, Leeuwarden, The Netherlands., Jonker JW; Department of Pediatrics, Section of Molecular Metabolism and Nutrition, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands., Brummelkamp TR; Oncode Institute, Division of Biochemistry, The Netherlands Cancer Institute, Amsterdam, The Netherlands. t.brummelkamp@nki.nl.
Jazyk: angličtina
Zdroj: Nature [Nature] 2023 Sep; Vol. 621 (7977), pp. 171-178. Date of Electronic Publication: 2023 Aug 30.
DOI: 10.1038/s41586-023-06497-4
Abstrakt: Triacylglycerols (TAGs) are the main source of stored energy in the body, providing an important substrate pool for mitochondrial beta-oxidation. Imbalances in the amount of TAGs are associated with obesity, cardiac disease and various other pathologies 1,2 . In humans, TAGs are synthesized from excess, coenzyme A-conjugated fatty acids by diacylglycerol O-acyltransferases (DGAT1 and DGAT2) 3 . In other organisms, this activity is complemented by additional enzymes 4 , but whether such alternative pathways exist in humans remains unknown. Here we disrupt the DGAT pathway in haploid human cells and use iterative genetics to reveal an unrelated TAG-synthesizing system composed of a protein we called DIESL (also known as TMEM68, an acyltransferase of previously unknown function) and its regulator TMX1. Mechanistically, TMX1 binds to and controls DIESL at the endoplasmic reticulum, and loss of TMX1 leads to the unconstrained formation of DIESL-dependent lipid droplets. DIESL is an autonomous TAG synthase, and expression of human DIESL in Escherichia coli endows this organism with the ability to synthesize TAG. Although both DIESL and the DGATs function as diacylglycerol acyltransferases, they contribute to the cellular TAG pool under specific conditions. Functionally, DIESL synthesizes TAG at the expense of membrane phospholipids and maintains mitochondrial function during periods of extracellular lipid starvation. In mice, DIESL deficiency impedes rapid postnatal growth and affects energy homeostasis during changes in nutrient availability. We have therefore identified an alternative TAG biosynthetic pathway driven by DIESL under potent control by TMX1.
(© 2023. The Author(s).)
Databáze: MEDLINE
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