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

Author

Listed:
  • Kasparas Petkevicius

    (AstraZeneca
    AstraZeneca)

  • Henrik Palmgren

    (AstraZeneca
    University of Gothenburg)

  • Matthew S. Glover

    (AstraZeneca)

  • Andrea Ahnmark

    (AstraZeneca)

  • Anne-Christine Andréasson

    (AstraZeneca)

  • Katja Madeyski-Bengtson

    (AstraZeneca)

  • Hiroki Kawana

    (The University of Tokyo
    Advanced Research & Development Programs for Medical Innovation (AMED-LEAP))

  • 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
    Advanced Research & Development Programs for Medical Innovation (AMED-LEAP))

  • Sonja Hess

    (AstraZeneca)

  • Grzegorz Sienski

    (AstraZeneca)

  • Marc Pilon

    (University of Gothenburg)

  • Mohammad Bohlooly-Y

    (AstraZeneca)

  • Marcello Maresca

    (AstraZeneca)

  • Xiao-Rong Peng

    (AstraZeneca)

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.

Suggested Citation

  • Kasparas Petkevicius & Henrik Palmgren & Matthew S. Glover & Andrea Ahnmark & Anne-Christine Andréasson & Katja Madeyski-Bengtson & Hiroki Kawana & Erik L. Allman & Delaney Kaper & Martin Uhrbom & Lis, 2022. "TLCD1 and TLCD2 regulate cellular phosphatidylethanolamine composition and promote the progression of non-alcoholic steatohepatitis," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33735-6
    DOI: 10.1038/s41467-022-33735-6
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    1. Songyuan Li & Nina Akrap & Silvia Cerboni & Michelle J. Porritt & Sandra Wimberger & Anders Lundin & Carl Möller & Mike Firth & Euan Gordon & Bojana Lazovic & Aleksandra Sieńska & Luna Simona Pane & M, 2021. "Universal toxin-based selection for precise genome engineering in human cells," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    2. Suneng Fu & Ling Yang & Ping Li & Oliver Hofmann & Lee Dicker & Winston Hide & Xihong Lin & Steven M. Watkins & Alexander R. Ivanov & Gökhan S. Hotamisligil, 2011. "Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity," Nature, Nature, vol. 473(7348), pages 528-531, May.
    3. John S. O’Neill & Akhilesh B. Reddy, 2011. "Circadian clocks in human red blood cells," Nature, Nature, vol. 469(7331), pages 498-503, January.
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