Synthesis and identification of lithocholic acid 3‐sulfate as RORγt ligand to inhibit Th17 cell differentiation. Issue 4 (21st February 2022)

• Record Type: Journal Article
• Authors: Xiao, Riping; Lei, Kawai; Kuok, Hioha; Deng, Wende; Zhuang, Yuxin; Tang, Yanqing; Guo, Zhengyang; Qin, Hongyan; Bai, Li‐Ping; Li, Ting
• Is Part Of: Journal of leukocyte biology. Volume 112:Issue 4(2022)
• Page Start: 835
• Page End: 843
• Publication Date: 2022-02-21
• Subjects: lithocholic 3‐sulfate -- RORγt -- Th17 cells; Leucocytes -- Periodicals; Reticulo-endothelial system -- Periodicals; 571.96
• DOI: 10.1002/JLB.1MA0122-513R
• Languages: English
• ISSNs: 0741-5400

Abstract

Abstract: Primary bile acids (BAs), products of cholesterol metabolism and clearance, are synthesized in the liver and released into the intestine to facilitate the digestion and absorption of lipids. BAs are further converted by gut commensal bacteria into secondary colonic BAs and the metabolism disorder is closely linked to cholestatic liver diseases via regulating immune response. However, the effect and underlying mechanism of these host‐microorganism biliary metabolites on T lymphocyte remain unclear. In the current study, we synthesized a sulfated product of lithocholic acid (LCA), lithocholic acid 3‐sulfate (LCA‐3‐S), and investigated the binding affinity of the BAs metabolites on RORγt, the transcription factor of IL‐17A. Our results demonstrated that the sulfate of LCA, LCA‐3‐S, exhibited better effect than its oxidated metabolite, 3‐oxo‐LCA, binding to RORγt. The results further demonstrated that LCA‐3‐S selectively suppressed Th17 cell differentiation without influence on Th1, Th2, and Treg cells. Collectively, we synthesized the sulfated biliary metabolite LCA‐3‐S and demonstrated that LCA‐3‐S selectively inhibited Th17 cell differentiation by targeting RORγt, indicating that metabolite disorder of BAs resulting in the decrease of LCA‐3‐S probably contributes to the pathogenesis of cholestatic liver diseases. Graphical Abstract: Bile acid (BA) synthesis and cholesterol clearance pathway. Regulation of BA synthesis by feedback mechanism and BA transport through enterohepatic circulation. In the liver, cholesterol is metabolized to primary BAs (CA, CDCA) via primary pathway and alternative pathway, and conjugated with glycine or taurine, converted to TCA, GCA, GCDCA, and TCDCA. Primary BAs are transported to intestine via biliary excretion, and converted to secondary BAs (DCA, UDCA, LCA) by gut commensal bacteria, and conjugated with glycine or taurine, converted to GDCA, TUDCA, GUDCA, and GLCA. As the most common secondary BA, LCA is also oxidized to 3‐oxo‐LCA, or reabsorbed to the hepatocytes and converted into LCA‐3‐S in the liver. After conjugation, BAs are again excreted into the bile duct, completing the enterohepatic circulation. In the study, we explored that the sulfate of LCA, LCA‐3‐S, could bind to RORγt resulting in selectively inhibitory effect on Th17 cell differentiation, which might contribute to the prevention of cholestatic liver diseases.