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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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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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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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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DOI: https://doi.org/10.1038/s42255-019-0066-3
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