Disruption of peroxisome proliferator-activated receptor α in hepatocytes protects against acetaminophen-induced liver injury by activating the IL-6/STAT3 pathway.
Disruption of peroxisome proliferator-activated receptor α in hepatocytes protects against acetaminophen-induced liver injury by activating the IL-6/STAT3 pathway.
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肝细胞中过氧化物酶体增殖物激活受体α的破坏可通过激活IL-6/STAT3途径来防止对乙酰氨基酚诱导的肝损伤
DOI：
10.7150/ijbs.69609
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发表时间：
2022
影响因子：
9.2
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Zhang Z;Yao T;Zhao N;Liu H;Cheng H;Gonzalez FJ;Wang H;Wang G;Qu A;Wang Y
背景与目的：过氧化物酶体增殖物激活受体α（PPARα）是一种配体激活转录因子，在肝脏中大量表达。此前曾有报道称 PPARα 激活剂可防止对乙酰氨基酚引起的肝毒性，但非诺贝特（一种激活 PPARα 的降脂药物）具有导致肝损伤的常见副作用。因此，肝脏 PPARα 对药物性肝损伤的确切作用仍不清楚。方法：肝细胞特异性Ppara基因敲除小鼠和同窝野生型对照小鼠腹腔注射对乙酰氨基酚（400 mg/kg体重）。在不同时间点收集血液和肝脏样本。我们通过逆转录酶定量 PCR、比色、免疫组织化学分析和蛋白质印迹测量了 I 期和 II 期细胞色素 P450 酶、谷胱甘肽、活性氧、细胞因子（包括 Il6）和 pSTAT3。结果：DILI 患者肝脏 PPARα 表达显着降低。肝细胞中 Ppara 基因的破坏显着减少了对乙酰氨基酚引起的小鼠肝损伤。与对照小鼠相比，给予对乙酰氨基酚后，肝细胞特异性 Ppara 敲除小鼠中 ROS 产生减少，而不是 I 期和 II 期细胞色素 P450 酶的表达水平减少。从机制上讲，与野生型小鼠相比，肝细胞特异性 Ppara 敲除小鼠上调了保肝途径 IL-6/STAT3 的激活，注射对乙酰氨基酚后，肝细胞特异性 Ppara 敲除小鼠的肝 IL6 mRNA 水平、肝蛋白 STAT3 和磷酸化 STAT3 水平远高于野生型小鼠。结论：肝细胞特异性破坏 Ppara 基因可通过减少氧化应激和上调保肝 IL-6/STAT3 信号通路来防止对乙酰氨基酚诱导的肝损伤。
Background & Aims: Peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor abundantly expressed in liver. PPARα activator has been previously reported to protect against acetaminophen-induced hepatotoxicity, but fenofibrate, a lipid-lowering drug that activates PPARα, has a common side-effect causing liver injury. Thus, the exact effect of liver PPARα on drug-induced liver injury remains obscure. Methods: Hepatocyte-specific Ppara knockout mice and littermate wild-type control mice were intraperitoneally injected with acetaminophen (400 mg/kg body weight). Blood and liver samples were collected at different time points. We measured phase I and II cytochrome P450 enzymes, glutathione, reactive oxygen species, cytokines including Il6, and pSTAT3 by reverse transcriptase quantitative PCR, colorimetric, immunohistochemistry analyses and Western blotting. Results: Hepatic expression of PPARα was significantly decreased in DILI patients. Disruption of the Ppara gene in hepatocytes significantly reduced acetaminophen-induced liver injury in mice. ROS production rather than the expression levels of phase I and II cytochrome P450 enzymes was reduced in hepatocyte-specific Ppara knockout mice compared to control mice after acetaminophen administration. Mechanistically, hepatocyte-specific Ppara knockout mice had upregulated activation of the hepatoprotective pathway IL-6/STAT3 compared to wild-type mice, as evidenced by hepatic Il6 mRNA levels, hepatic protein levels of STAT3 and phosphorylated STAT3 were much higher in hepatocyte-specific Ppara knockout mice than in wild-type mice post acetaminophen injection. Conclusions: Hepatocyte-specific disruption of the Ppara gene protects against acetaminophen-induced liver injury by reducing oxidative stress and upregulating the hepatoprotective IL-6/STAT3 signaling pathway.
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影响因子：
4.1
作者：
Chen, Chi;Krausz, Kristopher W.;Shah, Yatrik M.;Idle, Jeffrey R.;Gonzalez, Frank J.
通讯作者：
Gonzalez, Frank J.
DOI：
10.1016/j.bbagrm.2016.03.007
发表时间：
2016-09-01
影响因子：
4.7
作者：
Kandel, Benjamin A.;Thomas, Maria;Zanger, Ulrich M.
通讯作者：
Zanger, Ulrich M.
影响因子：
5.9
作者：
Jaeschke H;McGill MR;Ramachandran A
通讯作者：
Ramachandran A
DOI：
10.1056/nejmct0708278
发表时间：
2008-07-17
期刊：
The New England journal of medicine
影响因子：
--
作者：
Heard KJ
通讯作者：
Heard KJ
影响因子：
29.4
作者：
Goldberg DS;Forde KA;Carbonari DM;Lewis JD;Leidl KB;Reddy KR;Haynes K;Roy J;Sha D;Marks AR;Schneider JL;Strom BL;Corley DA;Lo Re V 3rd
通讯作者：
Lo Re V 3rd