Li Bo, He Xinglishang, Lei Shan-Shan, Zhou Fu-Chen, Zhang Ning-Yu, Chen Ye-Hui, Wang Yu-Zhi, Su Jie, Yu Jing-Jing, Li Lin-Zi, Zheng Xiang, Luo Rong, Kołodyńska Dorota, Xiong Shan, Lv Gui-Yuan, Chen Su-Hong
Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, China.
College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, China.
Front Pharmacol. 2020 Jan 31;10:1677. doi: 10.3389/fphar.2019.01677. eCollection 2019.
N-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) biosynthesis, results in hypertension and liver injury. This study aimed at investigating the changes of liver lipometabonomics and exploring the underlying mechanisms of liver injury in the L-NAME-treated rats. The male Sprague-Dawley (SD) rats were treated with L-NAME (40 mg/kg, p.o.) for 8 weeks. After that, the liver, aorta, fecal, and serum were collected for analysis. The results showed that L-NAME induced hypertension and disordered the endothelial nitric oxide synthase (eNOS)-NO pathway in the treated rats. L-NAME could also increase the levels of serum total cholesterol (TC), triglyceride (TG), alanine transaminase (ALT), and aspartate transaminase (AST). The multidimensional mass spectrometry-based shotgun lipidomics (MDMS-SL) analysis showed that L-NAME could induce significant changes of the total hepatic lipids and most hepatic triglycerides, as well as fatty acid (FA). A positive correlation was found between the blood pressure and TAG. Immunofluorescence and Western-Blot experiments indicated that the L-NAME treatment significantly influenced some FA β-oxidation, desaturation, and synthesis-related proteins. The increase of intestinal inflammation, decrease of microcirculation and tight junction proteins, as well as alterations of microbial communities were observed in the L-NAME induced hypertensive rats, as well as alterations of microbial communities were notable correlation to TAG and FA species. This study demonstrated that the L-NAME-induced hypertensive rats exhibiting liver injury were the joint action of hepatic abnormal fatty acid metabolism and microcirculation disorder. Furthermore, the gut microflora, as well as the changes of FA β-oxidation (ACOX, CPT1α), desaturation (SCD-1), and synthesis (FAS) may be the potential mechanisms for abnormal fatty acid metabolism.
N-硝基-L-精氨酸甲酯（L-NAME）是一种一氧化氮（NO）生物合成抑制剂，可导致高血压和肝损伤。本研究旨在调查L-NAME处理大鼠肝脏脂质代谢组学的变化，并探索肝损伤的潜在机制。雄性Sprague-Dawley（SD）大鼠用L-NAME（40mg/kg，口服）处理8周。之后，收集肝脏、主动脉、粪便和血清进行分析。结果表明，L-NAME诱导处理大鼠出现高血压并扰乱内皮型一氧化氮合酶（eNOS）-NO途径。L-NAME还可增加血清总胆固醇（TC）、甘油三酯（TG）、丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）水平。基于多维质谱的鸟枪法脂质组学（MDMS-SL）分析表明，L-NAME可诱导肝脏总脂质、大多数肝脏甘油三酯以及脂肪酸（FA）发生显著变化。发现血压与TAG之间呈正相关。免疫荧光和蛋白质免疫印迹实验表明，L-NAME处理显著影响一些与FAβ-氧化、去饱和及合成相关的蛋白质。在L-NAME诱导的高血压大鼠中观察到肠道炎症增加、微循环和紧密连接蛋白减少以及微生物群落改变，并且微生物群落的改变与TAG和FA种类显著相关。本研究表明，L-NAME诱导的出现肝损伤的高血压大鼠是肝脏异常脂肪酸代谢和微循环障碍共同作用的结果。此外，肠道微生物群以及FAβ-氧化（ACOX、CPT1α）、去饱和（SCD-1）和合成（FAS）的变化可能是脂肪酸代谢异常的潜在机制。
