Evaluation of the immortalized primary human hepatocyte cell line Fa2N-4 as a model for MASLD

Methods

We performed a comparative analysis of Fa2N-4 and HepG2 cells, assessing genomic architecture, lipid-induced steatosis, and pharmacological responsiveness. Results: The two models exhibited pronounced differences, including distinct karyotypes, divergent MASLD-associated genetic risk variant profiles, and markedly different transcriptional responses to lipid loading and drug treatment. We further examined the hepatic response to resmetirom, the first U.S. Food and Drug Administration (FDA) approved medication specifically for treating MASH.

Resmetirom, a thyroid hormone receptor-β agonist, reduced intracellular triglyceride accumulation in Fa2N-4 cells, but not in HepG2 cells, and this was accompanied by induction of mitochondrial glycolysis and oxidative phosphorylation pathways. Conclusions: Together, these findings demonstrate that hepatocyte model selection critically influences experimental outcomes in MASLD research and highlight Fa2N-4 cells as a physiologically relevant platform for mechanistic and translational studies of MASLD therapeutics.