Patatin-like phospholipase domain-containing protein 3 I148M variant (PNPLA3 I148M)

Patatin-like phospholipase domain-containing protein 3 (PNPLA3), also known as adiponutrin, is a membrane-bound enzyme primarily localized to the surface of lipid droplets in hepatocytes and adipocytes (UniProt Q9NST1). It possesses both triacylglycerol lipase and acyltransferase activities, playing a vital role in the mobilization and remodeling of triglycerides. The I148M variant, caused by a cytosine-to-guanine substitution (rs738409), is the most significant genetic risk factor for the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD) and its more severe form, MASH (Romeo et al., 2008, PMID: 18818369). This mutation results in a loss of hydrolase activity and causes the mutant protein to accumulate on lipid droplets, where it evades proteasomal degradation and physically hinders other lipases from accessing the lipid core (Smagris et al., 2015, PMID: 25533234). Because the I148M variant exerts a gain-of-toxic-function effect, therapeutic strategies focus on silencing the PNPLA3 gene rather than restoring its activity. Current clinical candidates, such as AZD2693 and ALN-PNP, utilize antisense oligonucleotides or siRNAs to degrade PNPLA3 mRNA, thereby reducing liver fat content and preventing the inflammatory progression toward cirrhosis and hepatocellular carcinoma (AstraZeneca; Alnylam Pharmaceuticals).

Other names

Adiponutrin I148Mrs738409 variantAcylglycerol O-acyltransferase PNPLA3i148m mutationCalcium-independent phospholipase A2-epsilon

Reduction of PNPLA3 protein expression through antisense oligonucleotide (ASO) or small interfering RNA (siRNA) mediated mRNA degradation to eliminate the gain-of-toxic-function mutant protein.