Poster #066, UCSF Benioff Children's Hospital Oakland
Using Mitochondrial partitioned Polygenic Risk Score to study MASLD phenotypes in response to Resmetirom in human iPSC-Derived Hepatocyte-like Cells
Mentors: Yuanyuan Qin, PhD & Marisa Medina, PhD
Metabolic dysfunction-associated steatotic liver disease (MASLD), the buildup of excess fat in the liver, is the most common chronic liver disease, affecting over 30% of the population. In 2024, Resmetirom became the first-ever drug approved by the FDA for the treatment of metabolic dysfunction-associated steatohepatitis (MASH) and MASLD. However, only ~30% of patients were responsive. Given the heterogeneity of MASLD, precision medicine approaches are needed to inform risk stratification and personalized treatment strategies. Major genes/SNPs (e.g., PNPLA3 and TM6SF2) contribute to MASLD; however, overall genetic factors contributing to MASLD progression or resmetirom response are largely unknown.
In this study, we calculated a mitochondria partitioned polygenic risk score (mtPRS) of MASLD from 15 loci in our POST cohort, and we aimed to investigate whether human induced Pluripotent Stem Cells (iPSC) derived hepatocyte-like cells (iHep) with high mtPRS will be less responsive to Resmetirom compared to the ones with low mtPRS. iPSCs from high (n=5) vs. low (n=5) mtPRS donors were differentiated into iPSC-iHeps. Mitochondrial activity, Mitochondrial oxidative stress, and Intracellular lipid accumulation in response to Resmetirom were measured and compared between high and low mtPRS lines. Mitochondrial activity was measured by determining the oxygen consumption rate (OCR) on a Seahorse Bioscience XFe96 extracellular flux analyzer. Mitochondrial oxidative stress was detected by MitoSox Red staining and live-cell imaging. Intracellular lipid accumulation was quantified with Bodipy 493/503 staining and live cell imaging.
We anticipate based on our preliminary analysis that iHeps with high mtPRS will be less responsive to Resmetirom, exhibiting impaired mitochondrial fatty acid beta-oxidation, increased oxidative stress and lipid accumulation compared to the low mtPRS ones. Our study will identify genetic factors that impact resmetirom response and improve MASLD clinical management.