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

Abstract

Cholestasis is a clinical syndrome triggered by the accumulation and aggregation of bile acids by subsequent inflammatory responses. The present study investigated the protective effect of glycyrrhetinic acid (GA) on the cholestatic liver injury induced by lithocholic acid (LCA) from both anti-inflammatory and choleretic mechanistic standpoints. Male C57BL/6 mice were treated with LCA twice daily for 4 days to induce intrahepatic cholestasis. GA (50 mg/kg) and pregnenolone 16α-carbonitrile (PCN, 45 mg/kg) were intraperitoneally injected 3 days before and throughout the administration of LCA, respectively. Plasma biochemical indexes were determined by assay kits, and hepatic bile acids were quantified by LC-MS/MS. Hematoxylin and eosin staining of liver sections was performed for pathological examination. Protein expression of the TLRs/NF-κB pathway and the mRNA levels of inflammatory cytokines and chemokines were examined by Western blotting and PCR, respectively. Finally, the hepatic expression of pregnane X receptor (PXR) and farnesoid X receptor (FXR) and their target genes encoding metabolic enzymes and transporters was evaluated. GA significantly reversed liver necrosis and decreased plasma ALT and ALP activity. Plasma total bile acids, total bilirubin, and hepatic bile acids were also remarkably preserved. More importantly, the recruitment of inflammatory cells to hepatic sinusoids was alleviated. Additionally, the protein expression of TLR2, TLR4, and p-NF-κBp65 and the mRNA expression of CCL2, CXCL2, IL-1β, IL-6, and TNF-α were significantly decreased. Moreover, GA significantly increased the expression of hepatic FXR and its target genes, including BSEP, MRP3, and MRP4. In conclusion, GA protects against LCA-induced cholestatic liver injury by inhibiting the TLR2/NF-κB pathway and upregulating hepatic FXR expression.

Lactiplantibacillus plantarum ATCC8014 Alleviates Postmenopausal Hypercholesterolemia in Mice by Remodeling Intestinal Microbiota to Increase Secondary Bile Acid Excretion

“…34 Elevated concentrations of LCA can the cause loss of intercellular junction proteins in hepatocytes, disrupt bile osmotic pressure gradients, reduce transmembrane movement of BAs, and ultimately accumulate in the liver, resulting in severe liver and gallbladder damage. 35 According to our findings, both DCA and LCA accumulated in the livers of ovariectomized hypercholesterolemic mice. However, after intervention with LP, the accumulation significantly decreased.…”

“…LCA, a highly hydrophobic secondary BA, enhances the expression of the ASBT and is preferentially transported from the intestinal epithelium to hepatocytes . Elevated concentrations of LCA can the cause loss of intercellular junction proteins in hepatocytes, disrupt bile osmotic pressure gradients, reduce transmembrane movement of BAs, and ultimately accumulate in the liver, resulting in severe liver and gallbladder damage . According to our findings, both DCA and LCA accumulated in the livers of ovariectomized hypercholesterolemic mice.…”

Secondary bile acids improve risk prediction for non‐invasive identification of mild liver fibrosis in nonalcoholic fatty liver disease

“…DCA and LCA) were more effectively activate TGR5, which is expressed in Kupffer cells and hepatic stellate cells (HSCs) 51,52 . LCA is considered to be hepatotoxic as the most hydrophobic BA, 53 and it has been used to produce a model of cholestatic liver damage 54 . Serving as a physiological sensor of LCA, the pregnane X receptor (PXR) could be activated to protect against the LCA‐induced liver damage 55 .…”

“…51,52 LCA is considered to be hepatotoxic as the most hydrophobic BA, 53 and it has been used to produce a model of cholestatic liver damage. 54 Serving as a physiological sensor of LCA, the pregnane X receptor (PXR) could be activated to protect against the LCA-induced liver damage. 55 However, experimental data revealed that LCA and its derivatives inhibit HSC activation and have anti-inflammatory and anti-fibrotic effects by inhibiting The connecting lines between dots represent the correlation, with red lines referring to positive correlation, and green lines referring to negative correlation.…”

A review of typical biological activities of glycyrrhetinic acid and its derivatives

“…Additionally, other hepatoprotective mechanisms are also discussed, such as the inhibition of the TLR/NF-κB pathway and upregulation of hepatic FXR to facilitate bile acid synthesis, transport, and detoxification, competitive inhibition of cyto P450 (CYP) enzymes responsible for the activation of pyrrolizidine alkaloid (PA) metabolism, particularly C3A1, which protects against liver damage, activation of PXR to regulate autophagy and lysosomal biogenesis, thereby alleviating acute liver injury, inhibition of hepatic stellate cell activation, and direct transcriptional inhibition of α2 (I) collagen gene (COL1A2), as observed in transgenic reporter mice, and other mechanisms. 147–150…”