Modulation of Disordered Bile Acid Homeostasis and Hepatic Tight Junctions Using Salidroside against Hepatocyte Apoptosis in Furan-Induced Mice.

Abstract

Furan, a processing-induced food contaminant, has attracted great attention due to its hepatotoxicity. To further investigate the underlying mechanism of salidroside (SAL) alleviating furan-induced liver damage, we divided Balb/c mice into the control group, the furan (8 mg/kg/day) group, and three groups of three different doses of SAL (10/20/40 mg/kg/day) in the current research. The shifted serum profile was observed through untargeted metabonomics, to which the bile acid metabolism was related, and the alleviating effect of SAL against furan-induced apoptosis was caused by the metabolism. Target bile acid quantification for the liver and serum showed that SAL positively regulated the homeostasis of bile acids disturbed by furan. Meanwhile, SAL significantly upregulated the synthesis genes of bile acids (Cyp7a1, Cyp7b1, Cyp8b1, and Cyp27a1) and the uptake transport genes (Ntcp and Oatps) and downregulated the efflux transport genes (Bsep, Ost-α, Ost-β, Mrp2, and Mrp4). Transmission electron microscopy of the bile canaliculi and tight junctions and the levels of tight junction marker proteins (ZO-1, occludin, and claudin-1) confirmed that the disruption of the hepatic tight junction was inhibited by SAL. The connection between the apoptosis- and tight junction-related proteins was observed through the construction of a protein-protein interaction network. SAL suppressed the furan-induced hepatocyte apoptosis evidenced by the detection of TUNEL and Bax, Bcl-2, and caspase-3 levels. Taken together, SAL alleviated furan-induced hepatocyte apoptosis via altering the disordered homeostasis of bile acids and hepatic tight junctions.