NAM J. 2026 Jul 30;2:100122. doi: 10.1016/j.namjnl.2026.100122. eCollection 2026.
ABSTRACT
Metabolic dysfunction associated steatotic liver disease (MASLD) is one of the most predominant liver disorders. MASLD is associated with dietary intake of fatty acids. Among them, oleic (OA) and palmitic (PA) acids are the most abundant. Furthermore, OA was reported to have an hepatoprotective effect against PA toxicity on primary hepatocytes and liver cell lines. In this work, to characterize the mechanisms related to fatty acids exposure, we analyzed the metabolomic signatures of HepG2/C3A using advanced organ-on-chip technology. The cells were exposed for 2 to 7 days to OA, PA and OA/PA mixture. The cell secretions were analyzed using GC-MS spectrometry to reveal their metabolomic signatures. We were able to identify a common HepG2/C3A response to OA, PA and OA/PA deciphering the FFAs global perturbations including the nitrogen metabolism, after 7 days of treatments. Then, we extracted the specificity of each treatment. We found that OA altered intracellular lipid secretion, while OA/PA shifted metabolism from the lipid production to their consumption. PA exposure induced changes consistent with a perturbation in oxidative stress, energy metabolism and a high oxalic acid production. Nicotinamide levels increased in all treatments, indicating a potential in vitro exposure biomarker of FFA, and a potential mechanistic candidate for further validation in preclinical and clinical settings as its protective effect against liver steatosis was reported in literature. These findings highlight the intricate metabolic responses to FFAs exposure in hepatocytes, suggesting potential biomarkers and pathways for liver-related disorders.
PMID:42603961 | PMC:PMC13476547 | DOI:10.1016/j.namjnl.2026.100122