Triclosan exposure induces liver fibrosis in mice: The heterogeneous nuclear ribonucleoprotein A1/pyruvate kinase M2 axis drives hepatic stellate cell activation

Abstract

Triclosan (TCS) is an effective broad-spectrum antibacterial agent. TCS possesses a stable structure, can easily accumulate in the environment, and may have numerous negative impacts on human health. One organ particularly susceptible to TCS damage is the liver; however, the molecular mechanisms underlying TCS-induced liver damage remain unclear. A long-term TCS exposure model was established in C57BL/6 mice through maternal administration from gestation to postnatal 8-week-old. The offspring were randomly assigned to three groups (0, 50, and 100 mg/kg TCS) with six animals per group, ensuring an equal gender distribution (3 males and 3 females). The results showed that TCS-exposed mice exhibited serum aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase enzyme activities increased by 1.5–2 times when compared with vehicle-treated mice, along with features of liver fibrosis. In the LX-2 cell line, used as an in vitro model, TCS promoted proliferation and migration and induced the activation of hepatic stellate cells (HSCs). The level of pyruvate kinase M2 (PKM2) dimer increased by 200 % in LX-2 cells treated with TCS. PKM2 dimer overexpression stimulated HSC activation, whereas treatment with TEPP-46 (a PKM2 dimer inhibitor) significantly decreased the activation process. The expression of heterogeneous ribonucleoprotein particle A1 (hnRNPA1) was upregulated in the TCS treatment group and promoted the PKM2 expression. Moreover, disruption of the hnRNPA1/PKM2 axis reduced HSC proliferation and migration activated by TCS. Overall, our findings highlighted that TCS could cause liver fibrosis by stimulating the proliferation and migration of HSCs activated via the hnRNPA1/PKM2 axis, providing promising treatment options for TCS-related liver damage.