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肝脏ZBTB22介导的解毒作用通过抑制孕烷X受体信号通路改善对乙酰氨基酚诱导的肝损伤。

Hepatic ZBTB22-mediated detoxification ameliorates acetaminophen-induced liver injury by inhibiting pregnane X receptor signaling.

作者信息

Chen Yingjian, Cui Tianqi, Xiao Shaorong, Li Tianyao, Zhong Yadi, Tang Kaijia, Guo Jingyi, Huang Shangyi, Chen Jiabing, Li Jiayu, Wang Qi, Huang Jiawen, Pan Huafeng, Gao Yong

机构信息

Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510080, China.

School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510080, China.

出版信息

iScience. 2023 Mar 2;26(4):106318. doi: 10.1016/j.isci.2023.106318. eCollection 2023 Apr 21.

DOI:10.1016/j.isci.2023.106318
PMID:36950116
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10025966/
Abstract

Overdose acetaminophen (APAP) can cause acute liver injury (ALI), but the underlying mechanism remains undetermined. This study explored the role of hepatic Zinc Finger And BTB Domain Containing 22 (ZBTB22) in defense against APAP-mediated hepatotoxicity. The results showed that hepatic ZBTB22 expression was significantly reduced in patients with ALI and mice. In mouse primary hepatocytes (MPHs), ZBTB22 deletion aggravated APAP overdose-induced ALI, whereas ZBTB22 overexpression attenuated that pathological progression. The results were further verified in ZBTB22 over-express or knockout mice models. In parallel, hepatocyte-specific ZBTB22 knockout also enhanced ALI. Furthermore, ZBTB22 decreased pregnane X receptor (PXR) expression, and the PXR activator pregnane-16α-carbonitrile suppressed the protective effect of ZBTB22 in APAP-induced ZBTB22-overexpressing mice. Collectively, our findings highlight the protective effect of ZBTB22 against APAP-induced ALI and unravel PXR signaling as the potential mechanism. Strategies to increase hepatic ZBTB22 expression represent a promising therapeutic approach for APAP overdose-induced ALI.

摘要

对乙酰氨基酚（APAP）过量可导致急性肝损伤（ALI），但其潜在机制仍未明确。本研究探讨了肝脏含锌指和BTB结构域蛋白22（ZBTB22）在抵御APAP介导的肝毒性中的作用。结果显示，ALI患者和小鼠的肝脏ZBTB22表达显著降低。在小鼠原代肝细胞（MPH）中，ZBTB22缺失加重了APAP过量诱导的ALI，而ZBTB22过表达减轻了该病理进程。这些结果在ZBTB22过表达或基因敲除小鼠模型中得到进一步验证。同时，肝细胞特异性ZBTB22基因敲除也增强了ALI。此外，ZBTB22降低了孕烷X受体（PXR）的表达，并且PXR激活剂孕烷-16α-腈抑制了ZBTB22在APAP诱导的ZBTB22过表达小鼠中的保护作用。总的来说，我们的研究结果突出了ZBTB22对APAP诱导的ALI的保护作用，并揭示了PXR信号传导作为潜在机制。增加肝脏ZBTB22表达的策略代表了一种有前景的治疗APAP过量诱导的ALI的方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e42b/10025966/18b7bab8cf9e/gr11.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e42b/10025966/fc0e8f914677/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e42b/10025966/bcf58244e91d/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e42b/10025966/08506b46a64e/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e42b/10025966/4bfc738fadf6/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e42b/10025966/35282fa8c862/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e42b/10025966/22e99c8c9db0/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e42b/10025966/e7b120ac03af/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e42b/10025966/d073f9279741/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e42b/10025966/21752147ebaf/gr8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e42b/10025966/0f8af687aec6/gr9.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e42b/10025966/18b7bab8cf9e/gr11.jpg

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