Impact of PNPLA3 I148M on alpha-1 antitrypsin deficiency-dependent liver disease progression

Background and Aims: Genetic risk factors are major determinants of chronic liver disease (CLD) progression. Patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M polymorphism and alpha-1 antitrypsin (AAT) E342K variant, termed PiZ, are major modifiers of metabolic CLD. Both variants are known to affect metabolic CLD through increased endoplasmic reticulum stress, but their combined effect on CLD progression remains largely unknown. Here, we aimed to test our working hypothesis that their combined incidence triggers CLD disease progression. Approach and Results: We showed that patients with PiZZ/PNPLA3(I148M) from the European alpha-1-antitrypsin deficiency (AATD) liver consortium and the UK Biobank had a trend towards higher liver enzymes, but no increased liver fat accumulation was evident between subgroups. After generating transgenic mice that overexpress the PiZ variant and simultaneously harbor the PNPLA3(I148M) knockin (designated as PiZ/PNPLA3(I148M)), we observed that animals with PiZ and PiZ/PNPLA3(I148M) showed increased liver enzymes compared to controls during aging. However, no significant difference between PiZ and PiZ/PNPLA3(I148M) groups was observed, with no increased liver fat accumulation over time. To further study the impact on CLD progression, a Western-styled diet was administered, which resulted in increased fat accumulation and fibrosis in PiZ and PiZ/PNPLA3(I148M) livers compared to controls, but the additional presence of PNPLA3(I148M) had no impact on liver phenotype. Notably, the PiZ variant protected PNPLA3(I148M) mice from liver damage and obesity after Western-styled diet feeding. Conclusion:Our results demonstrate that the PNPLA3 polymorphism in the absence of additional metabolic risk factors is insufficient to drive the development of advanced liver disease in severe AATD.