TLCD1 and TLCD2 regulate cellular phosphatidylethanolamine composition and promote the progression of non-alcoholic steatohepatitis

Kasparas Petkevicius (), Henrik Palmgren, Matthew S. Glover, Andrea Ahnmark, Anne-Christine Andréasson, Katja Madeyski-Bengtson, Hiroki Kawana, Erik L. Allman, Delaney Kaper, Martin Uhrbom, Liselotte Andersson, Leif Aasehaug, Johan Forsström, Simonetta Wallin, Ingela Ahlstedt, Renata Leke, Daniel Karlsson, Hernán González-King, Lars Löfgren, Ralf Nilsson, Giovanni Pellegrini, Nozomu Kono, Junken Aoki, Sonja Hess, Grzegorz Sienski, Marc Pilon, Mohammad Bohlooly-Y, Marcello Maresca and Xiao-Rong Peng
Additional contact information
Kasparas Petkevicius: AstraZeneca
Henrik Palmgren: AstraZeneca
Matthew S. Glover: AstraZeneca
Andrea Ahnmark: AstraZeneca
Anne-Christine Andréasson: AstraZeneca
Katja Madeyski-Bengtson: AstraZeneca
Hiroki Kawana: The University of Tokyo
Erik L. Allman: AstraZeneca
Delaney Kaper: University of Gothenburg
Martin Uhrbom: AstraZeneca
Liselotte Andersson: AstraZeneca
Leif Aasehaug: AstraZeneca
Johan Forsström: AstraZeneca
Simonetta Wallin: AstraZeneca
Ingela Ahlstedt: AstraZeneca
Renata Leke: AstraZeneca
Daniel Karlsson: AstraZeneca
Hernán González-King: AstraZeneca
Lars Löfgren: AstraZeneca
Ralf Nilsson: AstraZeneca
Giovanni Pellegrini: AstraZeneca
Nozomu Kono: The University of Tokyo
Junken Aoki: The University of Tokyo
Sonja Hess: AstraZeneca
Grzegorz Sienski: AstraZeneca
Marc Pilon: University of Gothenburg
Mohammad Bohlooly-Y: AstraZeneca
Marcello Maresca: AstraZeneca
Xiao-Rong Peng: AstraZeneca

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract The fatty acid composition of phosphatidylethanolamine (PE) determines cellular metabolism, oxidative stress, and inflammation. However, our understanding of how cells regulate PE composition is limited. Here, we identify a genetic locus on mouse chromosome 11, containing two poorly characterized genes Tlcd1 and Tlcd2, that strongly influences PE composition. We generated Tlcd1/2 double-knockout (DKO) mice and found that they have reduced levels of hepatic monounsaturated fatty acid (MUFA)-containing PE species. Mechanistically, TLCD1/2 proteins act cell intrinsically to promote the incorporation of MUFAs into PEs. Furthermore, TLCD1/2 interact with the mitochondria in an evolutionarily conserved manner and regulate mitochondrial PE composition. Lastly, we demonstrate the biological relevance of our findings in dietary models of metabolic disease, where Tlcd1/2 DKO mice display attenuated development of non-alcoholic steatohepatitis compared to controls. Overall, we identify TLCD1/2 proteins as key regulators of cellular PE composition, with our findings having broad implications in understanding and treating disease.

Date: 2022
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DOI: 10.1038/s41467-022-33735-6

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