Oleanolic Acid and Ursolic Acid Induce UGT1A1 Expression in HepG2 Cells by Activating PXR Rather Than CAR
Oleanolic Acid and Ursolic Acid Induce UGT1A1 Expression in HepG2 Cells by Activating PXR Rather Than CAR
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齐墩果酸和熊果酸通过激活 PXR 而不是 CAR 诱导 HepG2 细胞中 UGT1A1 表达
DOI：
10.3389/fphar.2019.01111
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发表时间：
2019-09
影响因子：
5.6
通讯作者：
Xia Chunhua
中科院分区：
文献类型：
--
作者：
Yao Na;Zeng Caiwen;Zhan Tao;He Fang;Liu Mingyi;Liu Fanglan;Zhang Hong;Xiong Yuqing;Xia Chunhua
背景：齐墩果酸（OA）及其异构体熊果酸（UA）最近因其生物活性而成为研究热点。我们之前证明UA可以抑制肝微粒体中UGT1A3和UGT1A4的活性，OA可以抑制肝微粒体中UGT1A3的活性。然而，OA和UA是否影响HepG2细胞中UGT1As的表达及其潜在的调节机制仍不清楚。目的：本研究旨在探讨OA和UA对HepG2细胞UGT1A表达的影响以及基于孕烷X受体（PXR）和组成型雄甾烷受体（CAR）信号通路对UGT1A1的调节机制。方法：我们通过 Q-PCR、Western blotting 和双荧光素酶报告基因检测分析了 OA 和 UA 对 HepG2 细胞、hPXR 沉默的 HepG2 细胞和 hCAR 沉默的 HepG2 细胞中 UGT1A 表达和 PXR/CAR 调节途径的影响。结果：在HepG2细胞中，OA和UA均显着诱导UGT1A1、UGT1A3、UGT1A4和UGT1A9的表达，并上调PXR的表达。然而，OA和UA并不影响CAR的表达。双荧光素酶报告基因检测显示，OA和UA可以显着促进PXR介导的UGT1A1荧光素酶活性，而OA和UA不影响CAR介导的UGT1A1荧光素酶活性。在 hPXR 沉默的 HepG2 细胞中，与对照组相比，OA 和 UA 并未提高 UGT1A1 活性。然而，与对照组或用 OA（10、20 和 40 μM）或 UA（10、20 和 40 μM）处理的非沉默 HepG2 细胞相比，hCAR 沉默的 HepG2 细胞中 UGT1A1 的表达显着升高。结论：OA和UA显着诱导HepG2细胞中UGT1A1、UGT1A3、UGT1A4和UGT1A9的表达，并且它们对UGT1A1的诱导是由PXR激活介导的，而不是CAR介导的。
Background: Oleanolic acid (OA) and its isomer ursolic acid (UA) have recently emerged as research foci based on their biologic activities. We previously demonstrated that UA can inhibit the activities of UGT1A3 and UGT1A4, and OA inhibits UGT1A3 activity in liver microsomes. However, whether OA and UA affect the expression of UGT1As in HepG2 cells and the underlying regulatory mechanism remain unclear. Purpose: The present study aimed to explore the effect of OA and UA on the expression of UGT1As in HepG2 cells and the regulatory mechanisms on UGT1A1 based on the pregnane X receptor (PXR) and constitutive androstane receptor (CAR) signaling pathways. Methods: We analyzed the effect of OA and UA on UGT1A expression and on the PXR/CAR regulatory pathway in HepG2 cells, hPXR-silenced HepG2 cells, and hCAR-silenced HepG2 cells by Q-PCR, Western blotting, and dual-luciferase reporter gene assays. Results: In HepG2 cells, OA and UA both significantly induced the expression of UGT1A1, UGT1A3, UGT1A4, and UGT1A9 and upregulated the expression of PXR. However, OA and UA did not affect CAR expression. A dual-luciferase reporter assay showed that OA and UA could markedly promote PXR-mediated UGT1A1 luciferase activity, whereas OA and UA did not affect CAR-mediated UGT1A1 luciferase activity. In hPXR-silenced HepG2 cells, OA and UA did not elevate UGT1A1 activity compared to the control group. However, the expression of UGT1A1 in hCAR-silenced HepG2 cells was markedly elevated compared to the control group or with non-silenced HepG2 cells treated with OA (10, 20, and 40 μM) or UA (10, 20, and 40 μM). Conclusions: OA and UA significantly induce the expression of UGT1A1, UGT1A3, UGT1A4, and UGT1A9 in HepG2 cells, and their induction on UGT1A1 is mediated by PXR activation, not CAR.
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DOI：
10.3109/00498254.2016.1156784
发表时间：
2017-01
期刊：
Xenobiotica; the fate of foreign compounds in biological systems
影响因子：
--
作者：
Street CM;Zhu Z;Finel M;Court MH
通讯作者：
Court MH
影响因子：
7.9
作者：
Hsiao-Yun, Chang;Chao-Jung, Chen;Yun-Ping, Lim
通讯作者：
Yun-Ping, Lim
影响因子：
5.8
作者：
Sugatani, J;Yamakawa, K;Miwa, M
通讯作者：
Miwa, M
影响因子：
3.4
作者：
Aguiriano-Moser V;Svejda B;Li ZX;Sturm S;Stuppner H;Ingolic E;Höger H;Siegl V;Meier-Allard N;Sadjak A;Pfragner R
通讯作者：
Pfragner R
影响因子：
--
作者：
S. Kapitanović;T. Ivkovic;G. Jakovljević;J. Giljević
通讯作者：
S. Kapitanović;T. Ivkovic;G. Jakovljević;J. Giljević