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Lipase tug of war: PNPLA3 sequesters ABHD5 from ATGL

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A common missense variant (I148M) in patatin-like phospholipase domain-containing protein 3 (PNPLA3) was strongly linked to human fatty liver disease in 2008, but the underlying mechanisms have since remained unclear. Compelling data from Yang et al., published in Nature Metabolism, suggest that PNPLA3 binds ABHD5, sequestering it and preventing it from activating ATGL, the major intracellular triglyceride lipase.

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Fig. 1: PNPLA3 (adiponutrin) sequesters ABHD5 (CGI-58) from binding and activating ATGL (PNPLA2).

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Authors and Affiliations

  1. Sahlgrenska Academy, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden

    Stefano Romeo

  2. Clinical Nutrition Unit, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy

    Stefano Romeo

  3. Cardiology Department, Sahlgrenska University Hospital, Gothenburg, Sweden

    Stefano Romeo

  4. Metabolic Research Laboratories, Wellcome Trust–MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK

    David B. Savage

Authors
  1. Stefano Romeo
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  2. David B. Savage
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Correspondence to Stefano Romeo or David B. Savage.

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Competing interests

S.R. has served as a consultant for Astra Zeneca, GSK, Pfizer, AMGEN, SANOFI, AKCEA therapeutics, Novo Nordisk, IONIS, CELGENE, MEDAcorp and CAMP4. S.R. has also received research grant funding from Astra-Zeneca, AMGEN and SANOFI. D.B.S. has no conflicts of interest to declare.

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Romeo, S., Savage, D.B. Lipase tug of war: PNPLA3 sequesters ABHD5 from ATGL. Nat Metab 1, 505–506 (2019). https://doi.org/10.1038/s42255-019-0067-2

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