PNPLA3

Patatin-domain lipid-droplet protein of the PNPLA family, most closely related to PNPLA2/ATGL, expressed mainly in liver and adipose tissue and strongly induced by feeding, insulin and carbohydrate. It is a single-pass type II membrane protein that partitions between the endoplasmic reticulum and the surface of lipid droplets, and it carries a Ser47/Asp166 catalytic dyad. Purified PNPLA3 hydrolyses triacylglycerol, diacylglycerol and monoacylglycerol with a preference for oleate and for polyunsaturated acyl chains, and also performs CoA-independent transacylation between acylglycerols; in hepatocytes it remodels the fatty-acid composition of the triacylglycerol pool rather than driving net lipolysis. Its triglyceride hydrolase activity is stimulated by ABHD5/CGI-58, the same co-activator that ATGL requires, and PNPLA3 binds ABHD5 more avidly than ATGL does and competes with ATGL for it, so PNPLA3 on the droplet surface restrains ATGL-mediated lipolysis. What the protein's dominant physiological reaction is remains unsettled: one group reports a CoA-dependent lysophosphatidic acid acyltransferase activity that another group, assaying the same reaction with a positive control, could not detect, and mice lacking PNPLA3 have no hepatic phenotype. The common I148M substitution is the strongest common genetic risk factor for steatotic liver disease. It reduces triglyceride hydrolase activity, but it also escapes ubiquitin-mediated degradation and accumulates on hepatic lipid droplets, and the three current mechanistic accounts of it differ fundamentally - loss of a polyunsaturated-triglyceride lipase that supplies VLDL secretion, gain of function through sequestration of ABHD5 away from ATGL, or a neomorphic activity that obstructs both ABHD5-dependent lipolysis and apolipoprotein B secretion.

Disorders

Relationship is the entry's genetic[].relationship_type. untyped means the entry has a genetic record for the gene but does not type it; its free-text association is shown instead.