Galactosylated Solid Lipid Nanoparticles with Swertiamarin Alleviate Cholestiatic Liver Injury via Enhancing the SIRT1/Nrf2 Pathway.

Swertiamarin (STM), one of the main bioactive compounds of Swertia plants, exerts its potential anti-CLI effects. The objective of this study was to prepare liver-targeting solid lipid nanoparticles (SLNs) with STM, using a galactosylated lipid, N-hexadecyl lactobionamide (N-HLBA), and evaluate its cholestatic effect on alpha-naphthylisothiocyanate (ANIT)-induced CLI. STM-loaded galactosylated SLN (STM@GalSLN) was prepared using the melt-emulsification-ultrasound method. The influence of STM@GalSLN on liver damage, oxidative stress, hepatocyte apoptosis, and Sirtuin 1 (SIRT1)/NF-E2 p45-related Factor 2 (Nrf2) pathway in ANIT-injured mice was evaluated. Also the cell survival, intracellular ROS, apoptotic rate, expression of SIRT1/Nrf2 pathway ralated proteins in ANIT-induced human liver HepG2 cells were measured. The mean diameter and zeta potential of STM@GalSLN was 167.30 nm and - 13.10 mV respectively. STM@GalSLN (100 mg/kg) alleviated ANIT-induced CLI in vivo, as evidenced by improved histopathology, decreased levels of liver biochemical indicators and cholestatic markers. Also STM@GalSLN (50 µM) notably increased cell survival, reduced ROS overproduction and apoptotic rate in ANIT-injured hepatocytes. Furthermore, STM@GalSLN significantly upregulated the protein expression levels of hepatic SIRT1, pNrf2, HO-1, and NQO1 during CLI. The protective effect of STM@GalSLN in vitro was blocked using EX-527 (10 mM), a selective SIRT1 inhibitor. Taken together, STM@GalSLN alleviated experimental CLI by enhancing the SIRT1/Nrf2 pathway.