Narirutin activates TFEB (transcription factor EB) to protect against Acetaminophen-induced liver injury by targeting PPP3/calcineurin
Narirutin activates TFEB (transcription factor EB) to protect against Acetaminophen-induced liver injury by targeting PPP3/calcineurin
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DOI：
10.1080/15548627.2023.2179781
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发表时间：
2023-02-26
期刊：
影响因子：
13.3
通讯作者：
Li, Xinwei
中科院分区：
文献类型：
--
作者：
Fang, Zhiyuan;Xu, Yanyong;Li, Xinwei
对乙酰氨基酚（APAP）过量是世界范围内药物性肝损伤的主要原因。巨噬/自噬-溶酶体途径（ALP）参与了APAP的肝毒性。TFEB（转录因子EB）促进自噬和溶酶体生物发生相关基因的表达，因此，药物激活TFEB介导的ALP可能是治疗apap诱导的肝损伤的有效方法。本研究旨在揭示从柑橘果皮中分离得到的主要生物活性成分narirutin （NR）对APAP肝毒性的影响，并探讨其作用机制。在APAP处理的小鼠中，NR可增强抗氧化酶活性，改善线粒体功能障碍，减轻肝损伤，而NR不影响APAP代谢和MAPK/JNK激活。NR增强TFEB转录活性，并以MTOR复合物1 （MTORC1）不依赖但PPP3/钙调磷酸酶依赖的方式激活ALP。此外，敲除Tfeb或敲除肝脏中PPP3CB/CNA2（蛋白磷酸酶3，催化亚基，β亚型）可消除NR对APAP过量的有益作用。机制上，NR通过PRO31、LYS61和PRO347残基与PPP3CB结合，增强PPP3/钙调磷酸酶活性，从而引发TFEB去磷酸化，促进ALP，减轻apap诱导的氧化应激和肝损伤。NR通过激活PPP3/钙调磷酸酶- tfeb - alp轴，对APAP诱导的肝损伤具有保护作用，表明NR可能是治疗APAP过量的潜在药物。
Acetaminophen (APAP) overdose is the predominant cause of drug-induced liver injury worldwide. The macroautophagy/autophagy-lysosomal pathway (ALP) is involved in the APAP hepatotoxicity. TFEB (transcription factor EB) promotes the expression of genes related to autophagy and lysosomal biogenesis, thus, pharmacological activation of TFEB-mediated ALP may be an effective therapeutic approach for treating APAP-induced liver injury. We aimed to reveal the effects of narirutin (NR), the main bioactive constituents isolated from citrus peels, on APAP hepatotoxicity and to explore its underlying mechanism. Administration of NR enhanced activities of antioxidant enzymes, improved mitochondrial dysfunction and alleviated liver injury in APAP-treated mice, whereas NR did not affect APAP metabolism and MAPK/JNK activation. NR enhanced TFEB transcriptional activity and activated ALP in an MTOR complex 1 (MTORC1)-independent but PPP3/calcineurin-dependent manner. Moreover, knockout of Tfeb or knockdown of PPP3CB/CNA2 (protein phosphatase 3, catalytic subunit, beta isoform) in the liver abolished the beneficial effects of NR on APAP overdose. Mechanistically, NR bound to PPP3CB via PRO31, LYS61 and PRO347 residues and enhanced PPP3/calcineurin activity, thereby eliciting dephosphorylation of TFEB and promoting ALP, which alleviated APAP-induced oxidative stress and liver injury. Together, NR protects against APAP-induced liver injury by activating a PPP3/calcineurin-TFEB-ALP axis, indicating NR may be a potential agent for treating APAP overdose.