Dataset Information

Altered Expression of Retinol Metabolism-Related Genes in an ANIT-Induced Cholestasis Rat Model.

ABSTRACT: Cholestasis is defined as a reduction of bile secretion caused by a dysfunction of bile formation. Insufficient bile secretion into the intestine undermines the formation of micelles, which may result in the reduced absorption of lipids and fat-soluble vitamins. Here, we investigated the retinol homeostasis and the alterations of retinol metabolism-related genes, including ?-carotene 15,15' monooxygenase (BCMO), lecithin:retinol acyltransferase (LRAT), aldehyde dehydrogenase (ALDH), cytochrome P450 26A1 (CYP26A1), and retinoic acid receptors (RAR) ?, in a ?-naphthyl isothiocyanate (ANIT)-induced cholestasis rat model. Moreover, we examined the expression of the farnesoid X receptor (FXR) target genes. Our results showed that plasma retinol levels were decreased in ANIT rats compared to control rats. On the contrary, hepatic retinol levels were not different between the two groups. The expression of FXR target genes in the liver and intestine of cholestasis model rats was repressed. The BCMO expression was decreased in the liver and increased in the intestine of ANIT rats compared to control rats. Finally, the hepatic expression of LRAT, RAR?, and ALDH1A1 in cholestatic rats was decreased compared to the control rats, while the CYP26A1 expression of the liver was not altered. The increased expression of intestinal BCMO in cholestasis model rats might compensate for decreased circulatory retinol levels. The BCMO expression might be regulated in a tissue-specific manner to maintain the homeostasis of retinol.

SUBMITTER: Takitani K

PROVIDER: S-EPMC6274878 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Altered Expression of Retinol Metabolism-Related Genes in an ANIT-Induced Cholestasis Rat Model.

Takitani Kimitaka K Kishi Kanta K Miyazaki Hiroshi H Koh Maki M Tamaki Hirofumi H Inoue Akiko A Tamai Hiroshi H

International journal of molecular sciences 20181026 11

Cholestasis is defined as a reduction of bile secretion caused by a dysfunction of bile formation. Insufficient bile secretion into the intestine undermines the formation of micelles, which may result in the reduced absorption of lipids and fat-soluble vitamins. Here, we investigated the retinol homeostasis and the alterations of retinol metabolism-related genes, including β-carotene 15,15' monooxygenase (BCMO), lecithin:retinol acyltransferase (LRAT), aldehyde dehydrogenase (ALDH), cytochrome P ...[more]

PMID: 30373117

Similar Datasets

Project description:Alpha-naphthylisothiocyanate (ANIT) causes intrahepatic cholestasis by injuring biliary epithelial cells. Adaptive regulation of hepatobiliary transporter expression has been proposed to reduce liver injury during cholestasis. Recently, the oxidative stress transcription factor Nrf2 (nf-e2-related factor 2) was shown to regulate expression of hepatobiliary transporters. The purpose of this study was to determine whether ANIT-induced hepatotoxicity and regulation of hepatobiliary transporters are altered in the absence of Nrf2. For this purpose, wild-type and Nrf2-null mice were administered ANIT (75 mg/kg po). Surprisingly, ANIT-induced hepatotoxicity was similar in both genotypes at 48 h. Accumulation of bile acids in serum and liver was lower in Nrf2-null mice compared with wild-types treated with ANIT. Transporter mRNA profiles differed between wild-type and Nrf2-null mice after ANIT. Bsep (bile salt export pump), Mdr2 (multidrug resistance gene), and Mrp3 (multidrug resistance-associated protein) efflux transporters were increased by ANIT in wild-type, but not in Nrf2-null mice. In contrast, mRNA expression of two hepatic uptake transporters, Ntcp (sodium-taurocholate cotransporting polypeptide) and Oatp1b2 (organic anion transporting peptide), were decreased in both genotypes after ANIT, with larger declines in Nrf2-null mice. mRNA expression of the transcriptional repressor of Ntcp, small heterodimeric partner (SHP), was increased in Nrf2-null mice after ANIT. Furthermore, hepatocyte nuclear factor 1alpha (HNF1alpha), which regulates Oatp1b2, was downregulated in ANIT-treated Nrf2-null mice. Preferential upregulation of SHP and downregulation of HNF1alpha and uptake transporters likely explains why Nrf2-null mice exhibited similar injury to wild-types after ANIT. A subsequent study revealed that treatment of mice with the Nrf2 activator oltipraz protects against ANIT-induced histological injury. Despite compensatory changes in Nrf2-null mice to limit ANIT toxicity, pharmacological activation of Nrf2 may represent a therapeutic option for intrahepatic cholestasis.

Project description:BackgroundPaeonia lactiflora Pall. (PLP), a traditional Chinese herbal medicine, has been used for hepatic disease treatment over thousands of years. In our previous study, PLP was shown to demonstrate therapeutic effect on hepatitis with severe cholestasis. The aim of this study was to evaluate the antioxidative effect of PLP on alpha-naphthylisothiocyanate (ANIT)-induced cholestasis by activating NF-E2-related factor 2 (Nrf2) via phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway.Materials and methodsLiquid chromatography-mass spectrometry (LC-MS) was performed to identify the main compounds present in PLP. The mechanism of action of PLP and its therapeutic effect on cholestasis, induced by ANIT, were further investigated. Serum indices such as total bilirubin (TBIL), direct bilirubin (DBIL), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), γ-glutamyl transpeptidase (γ-GT), and total bile acid (TBA) were measured, and histopathology of liver was also performed to determine the efficacy of treatment with PLP. Moreover, in order to illustrate the underlying signaling pathway, liver glutathione (GSH) content and mRNA or protein levels of glutamate-cysteine ligase catalytic subunit (GCLc), glutamate-cysteine ligase modulatory subunit (GCLm), Akt, heme oxygenase-1 (HO-1), NAD(P)H/quinone oxidoreductase 1 (Nqo1), and Nrf2 were further analyzed. In addition, validation of PLP putative target network was also performed in silico.ResultsFour major compounds including paeoniflorin, albiflorin, oxypaeoniflorin, and benzoylpaeoniflorin were identified by LC-MS analysis in water extract of PLP. Moreover, PLP could remarkably downregulate serum levels of TBIL, DBIL, AST, ALT, ALP, γ-GT, and TBA, and alleviate the histological damage of liver tissue caused by ANIT. It enhanced antioxidative system by activating PI3K/Akt/Nrf2 pathway through increasing Akt, Nrf2, HO-1, Nqo1, GCLc, and GCLm expression. The putative targets network validation also confirmed the important role of PLP in activating Akt expression.ConclusionThe potential mechanism of PLP in alleviating ANIT-induced cholestasis could to be related to the induction of GSH synthesis by activating Nrf2 through PI3K/Akt-dependent pathway. This indicates that PLP might be a potential therapeutic agent for cholestasis.

Dataset Information

Altered Expression of Retinol Metabolism-Related Genes in an ANIT-Induced Cholestasis Rat Model.

Publications

Altered Expression of Retinol Metabolism-Related Genes in an ANIT-Induced Cholestasis Rat Model.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets