Inhibiting DPP4 activity protects hiPSC-derived steatotic HLCs by supporting fatty acid and purine metabolism and dampening inflammation
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Background Metabolic dysfunction-associated steatotic liver disease (MAFLD) has a high prevalence and high co-morbidity for other diseases. Due to the complexity of this multifactorial disease, therapy options are still rather limited. We employed an in vitro pluripotent stem cell-based model to decipher basic disease-associated molecular pathways and to study the mode of action of potential drugs. Methods We induced the steatosis phenotype in human induced pluripotent stem cell (iPSC) derived hepatocyte-like cells (HLCs) by oleic acid (OA)-feeding and confirmed regulation of clinically relevant pathways by NGS-based global transcriptomic analyses. Analysis of the secretome of steatotic HLCs revealed Dipeptidyl peptidase 4 (DPP4) as a potential key mediator of the disease. To further elucidate its role in the development of MAFLD, we inhibited DPP4 activity with Vildagliptin (VILDA) and analyzed the global transcriptome changes as well as specific gene and protein expression of steatosis-associated genes with and without DPP4 inhibition. Results MAFLD-associated pathways such as PPAR- and TNF signaling were differentially regulated in hiPSC-derived steatotic HLCs. We found increased hepatic DPP4 activity and secretion upon OA. Fatty acid and purine metabolism and inflammation response pathways were improved upon DPP4 inhibition. Conclusions Our HLC-model confirmed clinically-relevant association of DPP4 with metabolism and inflammation which foster the development of MAFLD. Inhibiting DPP4 with VILDA partially relieved the steatotic phenotype. Trial registration Not applicable Impact and implications: Given the difficulties of identifying suitable anti-MAFLD drugs, novel model systems are urgently needed. Our in vitro HLC-model reproduced DPP4-dependent aspects of the disease and responded positively to Vildagliptin treatment. Further elucidation of the role of DPP4 in the etiology of MAFLD is warranted.
