Exploring genetic predisposition for anti-MASH drug response in a human stem cell-based in vitro model

Metabolic dysfunction-associated steatohepatitis (MASH) has emerged over the past decade as a major cause of morbidity and mortality. The socio-economic burden associated with MASH is booming, considering that the global prevalence is being estimated at 5% and no approved drug is available. Our group recently demonstrated that genetic predisposition may not only impact the pathogenesis of MASH, but also the response to certain treatments. Considering this pharmacogenetic background, we aimed to investigate the impact of a polygenic risk score for hepatic fat content (PRS-HFC) on the potential anti-steatotic effects of anti-MASH drug candidates (e.g., Aramchol, Nidufexor) using an in vitro population-based approach.
The PRS-HFC was determined for 84 human skin-derived precursor (hSKP)-cell lines isolated from different donors, based on the presence of single nucleotide polymorphisms in four genes, namely patatin-like phospholipase domain-containing protein 3 rs738409 C>G, transmembrane 6 superfamily member 2 rs58542926 C>T, glucokinase regulator rs1260326 C>T and membrane bound O-acyltransferase domain-containing 7 rs641738 C>T. Using the PRS-HFC, donors were classified in three risk categories (RC1 low, RC2 intermediate, RC3 high risk) and five cell lines were selected from each category to be differentiated to hepatic progenitor-like cells (hSKP-HPC). The cultures were then exposed for 24 hours to MASH triggers and anti-MASH drug candidates. Neutral lipid load was quantified using flow cytometry and visualized using fluorescence microscopy.
RC3 hSKP-HPCs exhibited a 3.5-fold higher lipid load in both control and MASH-triggered conditions compared to RC1 cultures, indicating that this system adequately represents the human in vivo population situation. In addition, the PRS-HFC positively correlated with the lipid-lowering effect of Aramchol (Pearson’s r = 0.66, p = 0.0147), suggesting an underlying genetic effect that will be further examined.
In conclusion, hSKP-HPC cultures can represent the genetic risk for hepatic fat accumulation and unveil a modifying effect of the PRS-HFC on the anti-steatotic effects of Aramchol, urging further mechanistic investigations.