Lycopene Alleviates Chronic Stress-Induced Liver Injury by Inhibiting Oxidative Stress-Mediated Endoplasmic Reticulum Stress Pathway Apoptosis in Rats
Lycopene Alleviates Chronic Stress-Induced Liver Injury by Inhibiting Oxidative Stress-Mediated Endoplasmic Reticulum Stress Pathway Apoptosis in Rats
复制标题
番茄红素通过抑制大鼠氧化应激介导的内质网应激途径凋亡来减轻慢性应激性肝损伤
DOI：
10.1021/acs.jafc.2c06650
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发表时间：
2022-11-01
影响因子：
6.1
通讯作者：
Fan, Honggang
中科院分区：
文献类型：
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作者：
Sun, Ning;Yang, Tianyuan;Fan, Honggang
肝脏是新陈代谢的主要器官，对慢性压力非常脆弱。番茄红素（LYC）是一种天然的类胡萝卜素，具有强大的抗氧化和慢性疾病的潜力。然而，LYC是否能保护慢性束缚应激（CRS）诱导的肝损伤及其机制尚不清楚。在这项研究中，大鼠被限制了21天，每天6小时，有或没有管饲LYC（10毫克/公斤）。CRS组血清ALT（85.99 +/- 4.07 U/L）和AST（181.78 +/- 7.35 U/L）以及肝损伤评分显著升高。LYC显著促进Nrf 2的核转位，提高抗氧化基因的表达，并减弱肝脏内的活性氧自由基（ROS）水平。细胞热位移分析（CETSA）和分子对接结果表明LYC与Keap 1竞争结合，最低亲和力为-9.0 kcal/mol。此外，LYC显着减轻肝内质网肿胀，降低内质网应激（ERS）标志物，如GRP 78，CHOP和切割的caspase-12的表达。同时，LYC还能减轻CRS诱导的肝细胞凋亡。有趣的是，每隔一天，腹腔注射Nrf 2抑制剂brusatol（0.4 mg/kg）显著抵消了LYC的保护作用。总之，LYC通过激活Nrf 2信号通路、清除ROS并进一步减弱ERS相关的凋亡通路来保护CRS诱导的肝损伤。
The liver is the major organ of metabolism and is extremely vulnerable to chronic stress. Lycopene (LYC) is a natural carotenoid with potent antioxidant and chronic disease potential. However, whether LYC protects against chronic restraint stress (CRS)-induced liver injury and the underlying mechanisms remain unclear. In this study, rats were restrained for 21 days for 6 h per day, with or without gavage of LYC (10 mg/kg). Serum ALT (85.99 +/- 4.07 U/L) and AST (181.78 +/- 7.35 U/L) and scores of liver injury were significantly increased in the CRS group. LYC significantly promoted the nuclear translocation of Nrf2, elevated the expression of antioxidant genes, and attenuated reactive oxygen radicals (ROS) levels within the liver. Cellular thermal shift assay (CETSA) and molecular docking results indicated that LYC competitively binds to Keap1 with the lowest molecule affinity of -9.0 kcal/mol. Moreover, LYC significantly relieved the hepatic endoplasmic reticulum swelling and decreased the expression of endoplasmic reticulum stress (ERS) hallmarks like GRP78, CHOP, and cleaved caspase-12. Meanwhile, LYC also mitigated CRS-induced hepatocyte apoptosis. Interestingly, every other day, the intraperitoneal injection of the Nrf2 inhibitor brusatol (0.4 mg/kg) significantly counteracted the protective effect of LYC. In conclusion, LYC protects against CRS-induced liver injury by activating the Nrf2 signaling pathway, scavenging ROS, and further attenuating ERS-associated apoptosis pathways.