PNPLA3 ^I148M is a novel regulator of bone mass independent of MASLD

Metabolic-dysfunction associated steatotic liver disease (MASLD) is the most common chronic liver disease. Fracture risk is increased among people with MASLD, however, the genetic contribution to risk is undetermined. PNPLA3 ^I148M is a common SNP which accounts for most MASLD heritability and increases MASLD morbidity and mortality. However, PNPLA3 ^I148M impact on bone is unexplored. To bridge this gap, we used a validated murine model of MASLD (DIAMOND mice) which received human PNPLA3 transgenes via adeno-associated vector serotype 8 (AAV8) and assessed bone morphology, cellularity, and transcriptomics. PNPLA3 ^I148M was expressed in bone and associated with bone loss, decreased bone formation, increased bone resorption, and increased bone marrow adiposity. PNPLA3 ^I148M reprogrammed the transcriptome in bone, enriching expression of pathways associated with fatty acid metabolism and hampering bone turnover. Notably, these findings occurred in the absence of MASLD. These findings suggest PNPLA3 ^I148M possesses an intrinsic deleterious skeletal role.