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CYP3A suppression during diet-induced nonalcoholic fatty liver disease is independent of PXR regulation

Zeng, Hang et al.

Chemico-biological interactions. Volume 308: (2019, August 1st); pp 185-193 -- Elsevier Ireland Ltd

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  • Title:
    CYP3A suppression during diet-induced nonalcoholic fatty liver disease is independent of PXR regulation
  • Author: Zeng, Hang;
    Lin, Yiming;
    Gong, Jiande;
    Lin, Sisi;
    Gao, Jianguo;
    Li, Chunxiao;
    Feng, Zemin;
    Zhang, Hong;
    Zhang, Jie;
    Li, Youming;
    Yu, Chaohui
  • Found In: Chemico-biological interactions. Volume 308: (2019, August 1st); pp 185-193
  • Journal Title: Chemico-biological interactions
  • Subjects: Biochimie--Périodiques; Biologie moléculaire--Périodiques; Toxicologie biochimique--Périodiques; Biochemistry--Periodicals; Toxicological chemistry--Periodicals; CYP3A--NALFD--PXR; Dewey: 572
  • Rights: Licensed
  • Publication Details: Elsevier Ireland Ltd
  • Abstract: Abstract Cytochrome P450 3A (CYP3A) activity is inhibited, and its expression is suppressed during many diseases, including nonalcoholic fatty liver disease (NAFLD). However, the mechanism is controversial. Here, we report that PXR may not take part in the downregulation of CYP3A during NAFLD. Hepatic CYP3A11 (major subtype of mouse CYP3A) mRNA and protein expression was significantly decreased in both mice fed a high-fat diet (HFD) for 8 weeks and palmitate (PA)-treated mouse primary hepatocytes. Similarly, in HepG2 cells, PA treatment significantly suppressed the CYP3A4 (major subtype of human CYP3A) mRNA level and promoter transcription activity. However, Western blotting analysis found an induction of PXR nuclear translocation during NAFLD in both in vivo and in vitro models. Moreover, immunofluorescence determination also found nuclear translocation effect of PXR by PA stimulation in HepG2 cells. In addition, the siRNA knockdown of PXR did not affect the suppressive effects of PA on the CYP3A4 promoter transcription activity and mRNA levels in HepG2 cells. Similarly, PXR knockdown also did not affect the suppressive effects of PA on CYP3A11 mRNA and protein expression levels in mouse primary hepatoctyes. Taken together, the results showed that the suppressive effect of CYP3A transcription was independent of PXR regulation. Highlights CYP3A expression is suppressed by NAFLD modelling. PXR translocation is induced by NAFLD modelling. PXR silence did not affect the suppressive effect of PA on CYP3A in vitro .
  • Identifier: System Number: ETOCvdc_100084375426.0x000001; Journal ISSN: 0009-2797; 10.1016/j.cbi.2019.05.038
  • Publication Date: 2019
  • Physical Description: Electronic
  • Shelfmark(s): 3155.500000
  • UIN: ETOCvdc_100084375426.0x000001

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