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ATGL is a biosynthetic enzyme for fatty acid esters of hydroxy fatty acids

Author

Listed:
  • Rucha Patel

    (Beth Israel Deaconess Medical Center and Harvard Medical School)

  • Anna Santoro

    (Beth Israel Deaconess Medical Center and Harvard Medical School)

  • Peter Hofer

    (University of Graz)

  • Dan Tan

    (Salk Institute for Biological Studies)

  • Monika Oberer

    (University of Graz)

  • Andrew T. Nelson

    (University of California-San Diego)

  • Srihari Konduri

    (University of California-San Diego)

  • Dionicio Siegel

    (University of California-San Diego)

  • Rudolf Zechner

    (University of Graz
    BioTechMed-Graz)

  • Alan Saghatelian

    (Salk Institute for Biological Studies)

  • Barbara B. Kahn

    (Beth Israel Deaconess Medical Center and Harvard Medical School)

Abstract

Branched fatty acid (FA) esters of hydroxy FAs (HFAs; FAHFAs) are recently discovered lipids that are conserved from yeast to mammals1,2. A subfamily, palmitic acid esters of hydroxy stearic acids (PAHSAs), are anti-inflammatory and anti-diabetic1,3. Humans and mice with insulin resistance have lower PAHSA levels in subcutaneous adipose tissue and serum1. PAHSA administration improves glucose tolerance and insulin sensitivity and reduces inflammation in obesity, diabetes and immune-mediated diseases1,4–7. The enzyme(s) responsible for FAHFA biosynthesis in vivo remains unknown. Here we identified adipose triglyceride lipase (ATGL, also known as patatin-like phospholipase domain containing 2 (PNPLA2)) as a candidate biosynthetic enzyme for FAHFAs using chemical biology and proteomics. We discovered that recombinant ATGL uses a transacylation reaction that esterifies an HFA with a FA from triglyceride (TG) or diglyceride to produce FAHFAs. Overexpression of wild-type, but not catalytically dead, ATGL increases FAHFA biosynthesis. Chemical inhibition of ATGL or genetic deletion of Atgl inhibits FAHFA biosynthesis and reduces the levels of FAHFA and FAHFA-TG. Levels of endogenous and nascent FAHFAs and FAHFA-TGs are 80–90 per cent lower in adipose tissue of mice in which Atgl is knocked out specifically in the adipose tissue. Increasing TG levels by upregulating diacylglycerol acyltransferase (DGAT) activity promotes FAHFA biosynthesis, and decreasing DGAT activity inhibits it, reinforcing TGs as FAHFA precursors. ATGL biosynthetic transacylase activity is present in human adipose tissue underscoring its potential clinical relevance. In summary, we discovered the first, to our knowledge, biosynthetic enzyme that catalyses the formation of the FAHFA ester bond in mammals. Whereas ATGL lipase activity is well known, our data establish a paradigm shift demonstrating that ATGL transacylase activity is biologically important.

Suggested Citation

  • Rucha Patel & Anna Santoro & Peter Hofer & Dan Tan & Monika Oberer & Andrew T. Nelson & Srihari Konduri & Dionicio Siegel & Rudolf Zechner & Alan Saghatelian & Barbara B. Kahn, 2022. "ATGL is a biosynthetic enzyme for fatty acid esters of hydroxy fatty acids," Nature, Nature, vol. 606(7916), pages 968-975, June.
  • Handle: RePEc:nat:nature:v:606:y:2022:i:7916:d:10.1038_s41586-022-04787-x
    DOI: 10.1038/s41586-022-04787-x
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    Cited by:

    1. Shuai Yan & Anna Santoro & Micah J. Niphakis & Antonio M. Pinto & Christopher L. Jacobs & Rasheed Ahmad & Radu M. Suciu & Bryan R. Fonslow & Rachel A. Herbst-Graham & Nhi Ngo & Cassandra L. Henry & Dy, 2024. "Inflammation causes insulin resistance in mice via interferon regulatory factor 3 (IRF3)-mediated reduction in FAHFA levels," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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