Prevention of D-GalN/LPS-induced ALI by 18β-glycyrrhetinic acid through PXR-mediated inhibition of autophagy degradation

Abstract

Acute liver injury (ALI) has multiple causes and results in liver dysfunction. Severe or persistent liver injury eventually leads to liver failure and even death. Pregnane X receptor (PXR)-null mice present more severe liver damage and lower rates of autophagy. 18β-glycyrrhetinic acid (GA) has been proposed as a promising hepatoprotective agent. We hypothesized that GA significantly alleivates D-GalN/LPS-induced ALI, which involved in PXR-mediated autophagy and lysosome biogenesis. We found that GA can significantly decrease hepatocyte apoptosis and increase the hepatic autophagy marker LC3-B. Ad-mCherry-GFP-LC3 tandem fluorescence, RNA-seq and real-time PCR indicated that GA may stabilize autophagosomes and lysosomes and inhibit autophagosome–lysosome fusion. Simultaneously, GA markedly activates PXR, even reversing the D-GalN/LPS-induced reduction of PXR and its downstream genes. In contrast, GA has a weak protective effect in pharmacological inhibition of PXR and PXR-null mice, which significantly affected apoptosis- and autophagy-related genes. PXR knockout interferes with the stability of autophagosomes and lysosomes, preventing GA reducing the expression of lysosomal genes such as Cst B and TPP1, and suppressing autophagy flow. Therefore, we believe that GA increases autophagy by inhibiting autophagosome–lysosome fusion and blocked autophagy flux via activation of PXR. In conclusion, our results show that GA activates PXR to regulate autophagy and lysosome biogenesis, represented by inhibiting autophagosome–lysosome fusion and stabilization of lysosome. These results identify a new mechanism by which GA-dependent PXR activation reduces D-GalN/LPS-induced acute liver injury.

Hepatoprotective Effects of Glycyrrhetinic Acid on Lithocholic Acid-Induced Cholestatic Liver Injury Through Choleretic and Anti-Inflammatory Mechanisms

“…The scheme of animal experiments was adapted from that of previous studies ( Zhang et al, 2015 ; Kong et al, 2018 ; Fan et al, 2019 ). The GA dose used here (50 mg/kg) was chosen based on the literature ( Sun et al, 2017 ; Wang et al, 2017 ; Wu et al, 2021 ) and our previous studies. Furthermore, GA at a dose of 50 mg/kg effectively protected against cholestatic liver injury ( Wang et al, 2017 ; Yan et al, 2021 ).…”

Role of nuclear pregnane X receptor in Cu-induced lipid metabolism and xenobiotic responses in largemouth bass (Micropterus salmoides)

“…PXR has also been shown to regulate liver autophagy and apoptosis pathways, thus having hepatoprotective effects in various liver injuries ( 44 , 45 ). PXR-null mice were reported to have more severe liver damage and suppressed autophagy flow in mice ( 46 ). By using PXR-specific agonist and inhibitor to intervene in autophagy in mice with liver injuries, increasement of the autophagy indexes LC3-B and P62 were observed as a response to agonist pretreatment ( 46 ).…”

“…PXR-null mice were reported to have more severe liver damage and suppressed autophagy flow in mice ( 46 ). By using PXR-specific agonist and inhibitor to intervene in autophagy in mice with liver injuries, increasement of the autophagy indexes LC3-B and P62 were observed as a response to agonist pretreatment ( 46 ). In the present study, pharmacologic activation of PXR by RIF mitigated liver injuries, as shown by the lower levels of hepatocyte vacuolation in the H&E staining.…”

Recent Advances Regarding the Molecular Mechanisms of Triterpenic Acids: A Review (Part II)

“…An in vitro and in vivo analysis of GA effects in liver injury revealed that GA increases autophagy by upregulating the LC3-B and P62 autophagy-related genes; however, the autophagy increase mainly relies on the activation of the Pregnane X receptor (PXR), a nuclear receptor involved in metabolism, detoxification, inflammation, oxidative stress. and apoptosis with a significant protective effect on liver, thereby inhibiting the autophagosome–lysosome fusion and blocking the autophagy flux ( Figure 12 ) [ 157 ].…”