Qingluotongbi formula regulates the LXRα-ERS-SREBP-1c pathway in hepatocytes to alleviate the liver injury caused by Tripterygium wilfordii Hook. f

Ethnopharmacological relevance: Tripterygium wilfordii Hook. f. (TW) is widely used to treat autoimmune and in-flammatory diseases; however, its development and application is limited by its significant association with liver injury. The compound formula Qingluotongbi (QLT) employs TW as its main component and is used to treat rheumatoid arthritis with no adverse reactions, suggesting that QLT may reduce the liver toxicity of TW.Aim of the study: We examined whether TW interferes with lipid metabolism to induce liver injury, and evaluated the protective effect of QLT in in vivo and in vitro experiments.Materials and methods: After administration of QLT and its ingredients, HepaRG cells and SD rats were tested for biochemical indicators, hepatocytes lipid changes, and rat liver pathological changes, and then we analyzed for the gene expression of liver X receptor alpha (LXR alpha), endoplasmic reticulum stress (ERS) key proteins, sterol regu-latory element binding protein-1c (SREBP-1c), and lipid-synthesizing enzymes. In HepaRG cells, the protein expression of glucose-regulated protein 78 kDa (GRP78) and LXR alpha was detected after addition of an LXR alpha in-hibitor, LXR alpha agonist, and ERS inhibitor. Results: TW caused significant elevation of biochemical indicators and lipid droplet deposition in hepatocytes, as well as upregulated the gene expression of LXR alpha, ERS key proteins, SREBP-1c, and lipid-synthesizing enzymes in both in vitro and in vivo settings, and caused liver injury in rats. QLT can alleviate the lipotoxic liver injury caused by TW. LXR alpha agonist further activated ERS induced by TW, whereas LXR alpha inhibitor significantly reduced ERS and lipotoxic injury induced by TW in HepaRG cells.Conclusions: TW upregulated LXR alpha to activate ERS and increased the gene expression of SREBP-1c and lipid-synthesizing enzymes, leading to increased lipid synthesis in hepatocytes to result in liver injury. QLT inhibi-ted the LXR alpha-ERS-SREBP-1c pathway and reduced abnormal lipid synthesis in hepatocytes and the hepatotox-icity of TW.

Automated summary

This study found that Tripterygium wilfordii can cause liver injury by interfering with lipid metabolism, and Qingluotongbi can protect against this toxic effect. Tripterygium wilfordii upregulates LXR alpha to activate endoplasmic reticulum stress (ERS) and increase lipid synthesis, while Qingluotongbi inhibits the LXR alpha-ERS-SREBP-1c pathway to reduce abnormal lipid synthesis and liver toxicity.