Cholestatic models induced by lithocholic acid and α‑naphthylisothiocyanate: Different etiological mechanisms for liver injury but shared JNK/STAT3 signaling

Abstract

α-naphthylisothiocyanate (aniT) is used to induce intrahepatic cholestasis and it is frequently used for investigations into the disease mechanism. The lithocholic acid (lca) cholestatic model has also been extensively used in various studies; however, to the best of our knowledge, a comparative study determining the hepatotoxic mechanisms induced by these two models has not been previously conducted. in the present study, icr mice were treated with aniT or lca to induce cholestatic liver injury. Biochemical analysis was used to determine the serum. alanine aminotransferase (alT), aspartate aminotransferase (aST), alkaline phosphatase (alP) and total bile acid (TBa) levels, and histopathological assessment was used to examine the liver tissue. Metabolomic analysis was used for the serum biomarker identification. reverse transcription-quantitative Pcr analysis and western blotting were used to analyze the inflammation biomarkers. The serum metabolome of the aniT group clustered away from of the lca group, which was demonstrated by the different modifications of the BA components. ALP level was found to be preferentially increased in the aniT group from 24 to 48 h. Total Ba levels was only increased in the aniT group at 24 h. in contrast, aST and alT activity levels were preferentially increased in the lca group. The bile ducts in the hepatic tissues of the aniT group were observed to be severely dilated, whereas the presence of edematous hepatocytes around the necrotic lesions and neutrophil infiltration were identified in the lca group. The expression levels of cholesterol 7α-hydroxylase and sterol 12α-hydroxylase genes were significantly downregulated in the ANIT group compared with the lca group, where a stronger adaptation of Ba metabolism was supported by major differences in the concentration of the Ba components. despite the aforementioned etiological differences in the cholestasis induced by each treatment, the activation of the JnK/STaT3 signaling pathway was similar between the two cholestatic models. in conclusion, these data suggested that the liver injury induced by aniT may be cholestatic, while the liver injury caused in the lca model may be hepatocellular. Moreover, the downstream cholestatic liver injury in both models was indicated to be mediated by the JnK/STaT3 signaling pathway.

Pregnane X Receptor and the Gut-Liver Axis: A Recent Update

“…The most hydrophobic secondary bile acid (BA) generated from dehydroxylation reactions by the gut microbiota is lithocholic acid (LCA), which is the most toxic BA to hepatocytes at high concentrations, such as during cholestasis (Fickert et al, 2006;Woolbright et al, 2014;Xu et al, 2020). Toxic levels of LCA and other secondary BAs produce liver damage through inflammation, oxidative stress, DNA damage, and cell death, leading to both liver and colon cancers (Allen et al, 2011;Ajouz et al, 2014;Woolbright et al, 2014;Jia and Jeon, 2019).…”

Promoter CAG is more efficient than hepatocyte‑targeting TBG for transgene expression via rAAV8 in liver tissues

“…no. CW2569M; CoWin Biosciences Co., Ltd.) as previously described (20). The rT temperature protocol was as follows: 25˚C for 5 min, 42˚C for 1 h, inactivation at 70˚C for 5 min and chilling at 4˚C for holding.…”

Lithocholic Acid Activates Mas-Related G Protein-Coupled Receptors, Contributing to Itch in Mice

“…Generally, LCA is regarded as a toxic compound that can induce liver damage. Oral administration of LCA into mice causes cholestatic liver injury via the JNK/STAT3 signaling pathway (Xu et al, 2020). Due to its detrimental effects, conventional LCA-related studies have focused on LCA-induced hepatotoxicity, which may account for the pathogenesis of liver injury and/or bile duct obstruction under cholestatic conditions (Fickert et al, 2006;Woolbright et al, 2014).…”