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Dynamic interactions of ABHD5 with PNPLA3 regulate triacylglycerol metabolism in brown adipocytes

Nature Metabolism volume 1, pages 560–569 (2019)Cite this article

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Abstract

Patatin-like phospholipase-domain-containing 2 (PNPLA2; also known as adipose triglyceride lipase, ATGL) and PNPLA3 (also known as adiponutrin) are encoded by close paralogues and appear to have opposite functions on triacylglycerol mobilization and storage. PNPLA2 is a major triglyceride lipase in adipose tissue and liver, whereas a common human variant of PNPLA3, I148M, greatly increases risk of hepatosteatosis. Nonetheless, the function of PNPLA3 and the mechanism by which the I148M variant promotes triacylglycerol accumulation are poorly understood. Here we demonstrate that PNPLA3 strongly interacts with α/β-hydrolase-domain-containing 5 (ABHD5; also known as CGI-58), an essential co-activator of PNPLA2. Molecular imaging experiments demonstrate that PNPLA3 effectively competes with PNPLA2 for ABHD5 and that PNPLA3 I148M competes even more effectively. Inducible overexpression of PNPLA3 I148M greatly suppressed PNPLA2-dependent lipolysis and triggered massive triacylglycerol accumulation in brown adipocytes, with these effects dependent on ABHD5. The interaction of PNPLA3 and ABHD5 can be regulated by fatty acid supplementation and synthetic ABHD5 ligands, raising the possibility that this interaction might be targeted for the treatment of fatty liver disease.

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Fig. 1: ABHD5 and PNPLA3 co-traffic to the ER.
Fig. 2: ABHD5 and PNPLA3 interact on ER structures and LDs.
Fig. 3: The interaction between ABHD5 and PNPLA3 is regulated by endogenous and synthetic ligands of ABHD5.
Fig. 4: PNPLA3 competes for ABHD5 and suppresses PNPLA2-dependent lipolysis.
Fig. 5: The I148M substitution in PNPLA3 enhances the interaction between ABHD5 and PNPLA3 on LDs.
Fig. 6: The I148M variant in PNPLA3 represents a gain-of-function mutation for suppressing ABHD5-dependent lipolysis.

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Data availability

All data generated or analysed during this study are included in this article and its supplementary information files or are available from the corresponding authors upon reasonable request.

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Acknowledgements

We thank J. Wang and M. Sanders for critical discussions and W. Liu for providing plasmids containing human PNPLA3. This work was supported by National Institutes of Health (NIH) grants, F30-DK116529-01A1 to A.Y., K99-DK114471 to E.P.M., and DK76629 and DK105963 to J.G.G. The Microscopy, Imaging and Cytometry Resources Core is supported, in part, by NIH Center grant P30 CA022453 to the Karmanos Cancer Institute at Wayne State University and the Perinatology Research Branch of the National Institutes of Child Health and Development at Wayne State University. The Lipidomics Core Facility at Wayne State University was supported in part by National Center for Research Resources, National Institutes of Health grant S10RR027926.

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  1. These authors contributed equally: Alexander Yang, Emilio P. Mottillo.

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  1. Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA

    Alexander Yang, Emilio P. Mottillo, Ljiljana Mladenovic-Lucas, Li Zhou & James G. Granneman

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Contributions

J.G.G. and E.P.M. conceived the experiments. J.G.G., E.P.M. and A.Y. designed the experiments. A.Y., E.P.M., L.Z. and L.M.L. conducted the experiments. A.Y., E.P.M. and J.G.G. analysed the data and wrote the manuscript. All authors read the manuscript and approved the final version.

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Correspondence to Emilio P. Mottillo or James G. Granneman.

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Yang, A., Mottillo, E.P., Mladenovic-Lucas, L. et al. Dynamic interactions of ABHD5 with PNPLA3 regulate triacylglycerol metabolism in brown adipocytes. Nat Metab 1, 560–569 (2019). https://doi.org/10.1038/s42255-019-0066-3

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