Global 
Deutschland 
Italia Liver and Bile
J Hepatol. 2025;82(5):871-881
PNPLA3(148M) is a gain-of-function mutation that promotes hepatic steatosis by inhibiting ATGL-mediated triglyceride hydrolysis
Background and aims: PNPLA3(148M) (patatin-like phospholipase domain-containing protein 3) is the most impactful genetic risk factor for steatotic liver disease. A key unresolved issue is whether PNPLA3(148M) confers a loss- or gain-of-function. Here the authors test the hypothesis that PNPLA3 causes steatosis by sequestering ABHD5 (α/β hydrolase domain-containing protein 5), the cofactor of ATGL (adipose TG lipase), thus limiting mobilization of hepatic triglyceride (TG).
Methods: They quantified and compared the physical interactions between ABHD5 and PNPLA3/ATGL in cultured hepatocytes using NanoBiT complementation assays and immunocytochemistry. Recombinant proteins purified from human cells were used to compare TG hydrolytic activities of PNPLA3 and ATGL in the presence or absence of ABHD5. Adenoviruses and adeno-associated viruses were used to express PNPLA3 in liver-specific Atgl-/- mice and to express ABHD5 in livers of Pnpla3M/M mice, respectively.
Results: ABHD5 interacted preferentially with PNPLA3 relative to ATGL in cultured hepatocytes. No differences were seen in the strength of the interactions between ABHD5 with PNPLA3(WT) and PNPLA3(148M). In contrast to prior findings, the authors found that PNPLA3, like ATGL, is activated by ABHD5 in in vitro assays using purified proteins. PNPLA3(148M)-associated inhibition of TG hydrolysis required that ATGL be expressed and that PNPLA3 be located on lipid droplets. Finally, overexpression of ABHD5 reversed the hepatic steatosis in Pnpla3M/M mice.
Conclusions: These findings support the premise that PNPLA3(148M) (patatin-like phospholipase domain-containing protein 3) is a gain-of-function mutation that promotes hepatic steatosis by accumulating on lipid droplets and inhibiting adipose triglyceride lipase-mediated lipolysis in an α/β hydrolase domain-containing protein 5 (ABHD5)-dependent manner. These results predict that reducing, rather than increasing, PNPLA3 expression will be the best strategy to treat PNPLA3(148M)-associated steatotic liver disease.