Frontiers in cell and developmental biology · 2026
DPP4 inhibition affects metabolism and inflammation associated pathways in hiPSC-derived steatotic HLCs.
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Loerch Christiane, Wruck Wasco, Wittich Annika, Hokamp Rabea, Reiss Julian, Pless Ole, Adjaye James, Graffmann Nina
Аннотация
INTRODUCTION: Metabolic dysfunction-associated steatotic liver disease (MAFLD) has a high prevalence and high comorbidity 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 potential disease-associated molecular pathways and study the mode of action of prospective drugs. Dipeptidyl peptidase 4 (DPP4) or cluster of differentiation 26 (CD26) is involved in inflammation, infections, immune disorders, type 2 diabetes, kidney disease, and cancer.
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 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 transcriptomic changes and specific gene and protein gene 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 feeding. Gene expression of fatty acid and purine metabolism and inflammation-associated pathways was regulated upon DPP4 inhibition.
DISCUSSION: Our HLC model confirmed the association of DPP4 with metabolism and inflammation, which foster the development of MAFLD. Inhibiting DPP4 activity with VILDA partially relieved the steatotic phenotype on a global transcriptomic level.
IMPACT AND IMPLICATIONS: Given the difficulties of identifying suitable anti-MAFLD drugs, novel model systems are urgently needed. Our in vitro HLC-model reproduced the DPP4-dependent aspects of the disease and responded positively to VILDA treatment. Further elucidation of the role of DPP4 in the etiology of MAFLD and other diseases is warranted.
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 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 transcriptomic changes and specific gene and protein gene 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 feeding. Gene expression of fatty acid and purine metabolism and inflammation-associated pathways was regulated upon DPP4 inhibition.
DISCUSSION: Our HLC model confirmed the association of DPP4 with metabolism and inflammation, which foster the development of MAFLD. Inhibiting DPP4 activity with VILDA partially relieved the steatotic phenotype on a global transcriptomic level.
IMPACT AND IMPLICATIONS: Given the difficulties of identifying suitable anti-MAFLD drugs, novel model systems are urgently needed. Our in vitro HLC-model reproduced the DPP4-dependent aspects of the disease and responded positively to VILDA treatment. Further elucidation of the role of DPP4 in the etiology of MAFLD and other diseases is warranted.