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Lipase tug of war: PNPLA3 sequesters ABHD5 from ATGL

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