Acetaminophen (APAP) is an antipyretic analgesic with high safety, but serious liver damage is observed in overdosed patients or in patients with risk factors. Recently, Niemann-Pick disease type A disease state may exacerbate APAP hepatotoxicity in animal and cellular model due to massive lysosomal lipid storage. Since intracellular cholesterol accumulation also occurs in Niemann-Pick disease type C (NPC), there is a concern that NPC also can be a risk factor for exacerbating the APAP hepatitis. In this study, we examined APAP hepatotoxicity in NPC model hepatocytes (HepG2 cells treated with several concentrations of U18666A (U18), an inhibitor of cholesterol transporter protein NPC) and in NPC model (Npc1 null) mice. We retrospectively evaluated the changes in liver function when APAP was used in NPC patients.
U18 treatment of cells altered the localization of intracellular cholesterol at all U18 concentrations, but the cholesterol content increased at high concentrations of U18, whereas it decreased at low concentrations of U18. APAP cytotoxicity was increased by both concentrations of U18, APAP cytotoxicity was increased in U18-treated cells in a U18 concentration-dependent manner. Although both concentrations of U18 altered the localization of cellular cholesterol, whereas cholesterol content was decreased in the lower concentrationsuggesting that intracellular cholesterol localization affects APAP toxicity. In mice model, the liver damage after APAP administration was milder in NPC mice than in WT mice. This may be due to the influence of liver inflammation derived from the pathogenesis of NPC on the results.Liver inflammation derived from NPC pathology may affect the results. NPC patient showed no changes in serum indicators suggesting the development of liver damage before and after the APAP use.
Our cellular resultsfindings  suggest that abnormal intracellular cholesterol dynamics in NPC can cause exacerbation of APAP liver injury, and this needs to be clarified using other mice model.