Identification of an alternative triglyceride biosynthesis pathway

Gian-Luca McLelland (), Marta Lopez-Osias, Cristy R. C. Verzijl, Brecht D. Ellenbroek, Rafaela A. Oliveira, Nicolaas J. Boon, Marleen Dekker, Lisa G. Hengel, Rahmen Ali, Hans Janssen, Ji-Ying Song, Paul Krimpenfort, Tim Zutphen, Johan W. Jonker and Thijn R. Brummelkamp ()
Additional contact information
Gian-Luca McLelland: The Netherlands Cancer Institute
Marta Lopez-Osias: The Netherlands Cancer Institute
Cristy R. C. Verzijl: University Medical Center Groningen, University of Groningen
Brecht D. Ellenbroek: The Netherlands Cancer Institute
Rafaela A. Oliveira: The Netherlands Cancer Institute
Nicolaas J. Boon: The Netherlands Cancer Institute
Lisa G. Hengel: The Netherlands Cancer Institute
Rahmen Ali: The Netherlands Cancer Institute
Hans Janssen: The Netherlands Cancer Institute
Ji-Ying Song: The Netherlands Cancer Institute
Paul Krimpenfort: The Netherlands Cancer Institute
Tim Zutphen: University Medical Center Groningen, University of Groningen
Johan W. Jonker: University Medical Center Groningen, University of Groningen
Thijn R. Brummelkamp: The Netherlands Cancer Institute

Nature, 2023, vol. 621, issue 7977, 171-178

Abstract: Abstract 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 pathologies1,2. 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 enzymes4, 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.

Date: 2023
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DOI: 10.1038/s41586-023-06497-4

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