Elafibranor restricts lipogenic and inflammatory responses in a human skin stem cell-derived model of NASH

Non-alcoholic steatohepatitis (NASH) is characterized by hepatocellular steatosis with concomitant hepatic inflammation. Currently, no tools exist that can adequately recapitulate the molecular mechanisms of NASH and assess the efficacy of potential anti-NASH drug candidates. The present study describes the development and application of a new preclinical model for NASH using hepatic cells generated from human skin-derived precursors (hSKP-HPC). Exposing these cells to lipogenic (insulin, glucose, fatty acids) and pro-inflammatory factors (IL-1β, TNF-α, TGF-β) resulted in a characteristic NASH response, including intracellular lipid accumulation, modulation of NASH-specific gene expression, increased caspase-3/7 activity and the secretion of inflammatory markers, such as CCL2, CCL5, CCL7, CCL8, CXCL5, CXCL8, IL1a, IL6 and IL11. The human relevance of the proposed NASH model was verified by transcriptomics analyses that revealed commonly modulated genes and identified the same gene classes between the in vitro system and patients suffering from NASH. The application potential of this in vitro model was demonstrated by testing elafibranor, a promising anti-NASH compound currently under clinical phase III trial evaluation. Elafibranor attenuated in vitro key features of NASH, and dramatically lowered lipid load as well as the expression and secretion of inflammatory chemokines, which in vivo are responsible for the recruitment of immune cells. This reduction in inflammatory response is NFκB-mediated. In summary, this human-relevant, sensitive in vitro system can be a valuable testing tool for the investigation of novel anti-NASH compounds. hSKP-HPC were exposed for 24h to lipogenic (insulin, glucose, fatty acids) and pro-inflammatory factors (IL-1β, TNF-α, TGF-β) in the abscence or presence of elafibranor, a PPAR-α/δ agonist. All experiments were conducted using three biological replicates: 'hSKP-HPC' control samples (n=3), 'hSKP-HPC NASH' samples (n=3), 'hSKP-HPC NASH' + elafibanor 10 µM samples (n=3) and 'hSKP-HPC NASH' + elafibanor 30 µM samples (n=3).