Effects of Yinzhihuang on Alleviating Cyclosporine A-Induced Cholestatic Liver Injury <i>via</i> Farnesoid X Receptor-Mediated Regulation of Transporters and Enzymes <i>in Vitro</i> and <i>in Vivo</i>

Abstract

Yinzhihuang (YZH), a traditional Chinese medicine prescription, was widely used to treat cholestasis. Cholestatic liver injury limited the use of the immunosuppressive drug cyclosporine A (CsA) in preventing organ rejection after solid organ transplantation. Clinical evidences suggested that YZH could enhance bile acids and bilirubin clearance, providing a potential therapeutic strategy against CsA-induced cholestasis. Nevertheless, it remains unclear whether YZH can effectively alleviate CsA-induced cholestatic liver injury, as well as the molecular mechanisms responsible for its hepatoprotective effects. The purpose of the present study was to investigate the hepatoprotective effects of YZH on CsA-induced cholestatic liver injury and explore its molecular mechanisms in vivo and vitro. The results demonstrated that YZH significantly improved the CsA-induced cholestatic liver injury and reduced the level of liver function markers in serum of Sprague-Dawley (SD) rats. Targeted protein and gene analysis indicated that YZH increased bile acids and bilirubin efflux into bile through the regulation of multidrug resistance-associated protein 2 (Mrp2), bile salt export pump (Bsep), sodium taurocholate cotransporting polypeptide (Ntcp) and organic anion transporting polypeptide 2 (Oatp2) transport systems, as well as upstream nuclear receptors farnesoid X receptor (Fxr). Moreover, YZH modulated enzymes involved in bile acids synthesis and bilirubin metabolism including Cyp family 7 subfamily A member 1 (Cyp7a1) and uridine 5'-diphosphate (UDP) glucuronosyltransferase family 1 member A1 (Ugt1a1). Furthermore, the active components geniposidic acid, baicalin and chlorogenic acid exerted regulated metabolic enzymes and transporters in LO2 cells. In conclusion, YZH may prevent CsAinduced cholestasis by regulating the transport systems, metabolic enzymes, and upstream nuclear receptors Fxr to restore bile acid and bilirubin homeostasis. These findings highlight the potential of YZH as a therapeutic intervention for CsA-induced cholestasis and open avenues for further research into its clinical applications.

Therapeutic Potential of Danyankang Capsule in High-Fat Diet-Induced Cholelithiasis and Its Impact on Liver FXR Signaling and Gut Microbiota

“…These isoforms are crucial in regulating bile acids, lipids, glucose metabolism, hepatic regeneration, and more. 7) Cholesterol, serving as the primary ingredient for bile acid synthesis, undergoes regulation chiefly by enzymes like CYP7A1, CYP8B1, and CYP27A1. These enzymes facilitate the conversion of cholesterol to primary bile acids in hepatocytes through intricate enzymatic reactions.…”

“…5,6) Farnesoid X receptor (FXR) stands as an important nuclear receptor in humans, orchestrating bile acid homeostasis, inflammation mitigation, and enterohepatic circulation. 7) Its intricate involvement extends to bile acid metabolism, cholesterol reversal functions, and hepatocyte protection. 8,9) A decrement in bile acid synthesis, majorly instigated by the SHP/RXRs/c-Jun N-terminal kinase (JNK)-c-Jun signaling cascade, and the therapeutic implications of FXR agonists, especially in quelling intestinal inflammation, have been documented.…”