Tanyu Tongzhi decoction regulates cholangiocyte-endothelial crosstalk to promote lipid reduction and liver function recovery for hyperlipidemic rats

BACKGROUND Hyperlipidemia is a common metabolic disorder and a core risk factor for cardiovascular and cerebrovascular diseases with suboptimal therapeutic outcomes.Tanyu Tongzhi decoction (TYTZD) lowers blood lipid levels, protects liver function, and alleviates symptoms in patients with hyperlipidemia and coronary heart disease.AIM To evaluate the anti-atherogenic and hepatoprotective effects of TYTZD on hyperlipidemia in rats and to explore its potential mechanisms.METHODS A hyperlipidemic rat model was established after 8 weeks of a high-fat diet in Sprague-Dawley rats.The administered doses of TYTZD were 3.6 g/kg/day, 7.2 g/kg/day, and 14.4 g/kg/day.Serum biochemical parameters and histopathological analyses were performed to determine the therapeutic effects of TYTZD.Ultra-high-performance liquid chromatography-tandem mass spectrometry, single-cell sequencing, network pharmacology, and targeted lipid metabolomics were used to elucidate the molecular mechanisms of the multi-component and multitarget interactions.Cell communication and molecular expression were verified in liver organoid-like constructs and hyperlipidemic rats.RESULTS TYTZD reduced blood lipid levels and restored liver function in hyperlipidemic rats.Analysis of the TYTZD components revealed that 33 metabolites were detected in the serum, whereas 44 different metabolite components were detected in the liver tissue of hyperlipidemic rats.Single-cell sequencing analysis of liver tissue revealed that multiple cell populations responded to TYTZD treatment, 4 / 63 including cholangiocytes and endothelial cells.Pseudotime analysis revealed continuous transcriptional state transitions among neutrophils, B cells, and pDCs.Kyoto Encyclopedia of Genes and Genomes analysis indicated that TYTZD may regulate the fluid shear stress and atherosclerosis pathway and the complement and coagulation cascades.The compounds distributed in the liver, tanshinone II A and scutellarin, form stable molecular-protein complexes with the differentially expressed molecules interleukin-6 and tumor necrosis factor-alpha in the target cells.Furthermore, TYTZD enhanced the crosstalk between liver cholangiocytes and endothelial cells, inhibited vascularization and inflammation, and attenuated lipotoxicity of liver cells in a liver organoid-like constructs model and in vivo.CONCLUSION TYTZD improves blood lipid levels and liver damage in hyperlipidemic rats by modulating cholangiocyte-endothelial crosstalk, inhibiting vascularization and inflammation, and improving lipid metabolism.In conclusion, this study revealed the molecular mechanisms underlying the hepatoprotective function of TYTZD, suggesting its therapeutic potential in hyperlipidemia.