Tributyl phosphate disrupts hepatic lipid metabolism via cGAS-STING signal pathway mediated inflammation

Tributyl phosphate (TBP) can lead to abnormal hepatic lipid metabolism. Inflammation triggered by the cGAS-STING may be involved in it. Within this research, we investigated the involved mechanisms of TBP-induced lipid metabolic disorders. Rats and BRL-3A cells are used as models to determine the liver toxicity of TBP. Aspirin was used to alleviate the inflammation induced by TBP. RU.521 and H151 were employed to inhibit the activation of cGAS-STING. HE staining was applied to observe liver injury. The mitochondrial structure was observed with transmission electron microscopy. The quantification of lipid levels was achieved through colorimetry. The concentrations of inflammatory factors were assessed by ELISA. The expression levels of genes involved in lipid metabolism and cGAS-STING signaling pathway were detected by Q-PCR and western blot. TBP induced hepatocyte swelling and disorganized cord structures of rat livers. Following exposure to TBP, there is an elevation in the concentrations of triglycerides (TG) and total cholesterol (T-CHO), and the mRNA and protein expression levels of FASN, SREBP2, and PPARγ also showed a significant increase(P < 0.05). TBP exposure enhanced interleukin-6 (IL-6) production and this effect is reversed by aspirin treatment(P < 0.05). In BRL-3A cells, inhibiting cGAS-STING signaling pathway decreased the IL-6 concentrations and reversed the lipid accumulation caused by TBP(P < 0.05). Taken together, our results suggest TBP induced histopathological damage in rat livers, including hepatocyte swelling and disorganized cord structures. It also caused alterations in mitochondrial structure. Moreover, TBP can mediate inflammatory responses via the cGAS-STING, which in turn leads to hepatic lipid accumulation.