PhD Student Federal University of Rio de Janeiro, Brazil
Abstract: Metabolic dysfunction-associated steatotic liver disease (MASLD) includes a spectrum of conditions that can progress in severity, potentially leading to fibrosis. Genetic factors, such as the PNPLA3 gene polymorphism (SNP), have been implicated in this progression. For MASLD progression studies, traditional biochemical tests often yield inconclusive results, while liver biopsy remains the gold standard, despite being invasive. This study aims to address these limitations by integrating omics-based techniques and induced pluripotent stem cells (iPSC) as an in vitro model to elucidate cellular, molecular and genetic mechanisms underlying MASLD severity. Patients were recruited from the Clementino Fraga Filho University Hospital (UFRJ) (CAAE: 16079319.0.0000.5257). Laboratory analyses included biochemical and coagulation profiles, while fibrosis severity was assessed via liver biopsy. Plasma samples were analyzed using bileomic to characterize bile acid profiles. PNPLA3 polymorphism (SNP) was determined through Sanger sequencing. The cohort consisted of 8 patients (2 male, 6 female) aged 47–77 years. Histopathological analysis revealed that four patients had absent or mild fibrosis, while the remaining exhibited advanced fibrosis. No significant differences in laboratory analyses were observed between these groups. Genetic analysis identified four patients with PNPLA3 SNP (three heterozygous, one homozygous). Advanced fibrosis was observed in one heterozygous and one homozygous patient, suggesting that PNPLA3 SNP may influence disease progression in the future. Bileomic analysis revealed a distinct toward bile acid profiles based on PNPLA3 SNP status, with SNP carriers exhibiting lower levels of the primary bile acid CDCA and its taurine conjugates, such as taurine conjugated CA. We highlight the potential of PNPLA3 SNP as a determinant of bile acid dysregulation and disease severity. Currently, iPSC from SNP and non-SNP patients are being generated. Future work includes developing iPSC-derived hepatocyte model to investigate the functional impact of genetic and clinical background. This research advances precision medicine by providing insights into MASLD pathophysiology and highlighting the utility of omics and iPSC for patient-specific approaches to diagnosis and treatment.
Funding Source: CNPq, FAPERJ, CAPES, INCT-REGENERA, MINISTÉRIO DA SAÚDE
