The NOX1 isoform of NADPH oxidase is involved in dysfunction of liver sinusoids in nonalcoholic fatty liver disease.
The NOX1 isoform of NADPH oxidase is involved in dysfunction of liver sinusoids in nonalcoholic fatty liver disease.
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DOI：
10.1016/j.freeradbiomed.2017.12.019
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发表时间：
2018-02-01
影响因子：
7.4
通讯作者：
Yabe-Nishimura C
中科院分区：
文献类型：
--
作者：
Matsumoto M;Zhang J;Zhang X;Liu J;Jiang JX;Yamaguchi K;Taruno A;Katsuyama M;Iwata K;Ibi M;Cui W;Matsuno K;Marunaka Y;Itoh Y;Torok NJ;Yabe-Nishimura C
活性氧（ROS）的产生增加被认为在非酒精性脂肪肝（NAFLD）的进展中起关键作用。然而，ROS的来源和NAFLD发展的潜在机制尚未建立。我们观察到非酒精性脂肪性肝炎（NASH）患者以及喂食高脂肪和高胆固醇（HFC）饮食8周的小鼠肝脏中NADPH氧化酶（NOX 1）的次要亚型显著上调。在Nox 1缺陷小鼠（Nox 1 KO）中，HFC饲料喂养的野生型小鼠（WT）中血清丙氨酸氨基转移酶和肝裂解半胱天冬酶-3水平的升高显著减弱。同时，增加的蛋白质硝基酪氨酸加合物，一个标记过氧亚硝酸盐诱导的损伤检测肝窦的野生型，在Nox 1 KO显着抑制。NOX 1 mRNA的表达在富集的肝窦内皮细胞（LSECs）的组分中比在肝细胞中高得多。在原代培养的LSEC中，棕榈酸（PA）上调NOX 1的mRNA水平，但不上调NOX 2或NOX 4。LSECs产生的一氧化氮在WT中被PA处理显著减弱，但在Nox 1 KO中没有。当在体外松弛TWNT 1，一种细胞系，起源于肝星状细胞，通过凝胶收缩试验进行了评估，松弛的星状细胞诱导的LSECs衰减PA治疗。相反，LSEC的松弛作用在从Nox 1 KO分离的细胞中得以保留。总之，LSEC中NOX 1的上调可能通过降低一氧化氮的生物利用度引起过氧亚硝酸盐介导的细胞损伤和受损的肝脏微循环。因此，来自NOX 1的ROS可能构成NAFLD进展的关键组分。
The increased production of reactive oxygen species (ROS) has been postulated to play a key role in the progression of nonalcoholic fatty liver disease (NAFLD). However, the source of ROS and mechanisms underlying the development of NAFLD have yet to be established. We observed a significant up-regulation of a minor isoform of NADPH oxidase, NOX1, in the liver of nonalcoholic steatohepatitis (NASH) patients as well as of mice fed a high-fat and high-cholesterol (HFC) diet for 8 weeks. In mice deficient in Nox1 (Nox1KO), increased levels of serum alanine aminotransferase and hepatic cleaved caspase-3 demonstrated in HFC diet-fed wild-type mice (WT) were significantly attenuated. Concomitantly, increased protein nitrotyrosine adducts, a marker of peroxynitrite-induced injury detected in hepatic sinusoids of WT, were significantly suppressed in Nox1KO. The expression of NOX1 mRNA was much higher in the fractions of enriched liver sinusoidal endothelial cells (LSECs) than in those of hepatocytes. In primary cultured LSECs, palmitic acid (PA) up-regulated the mRNA level of NOX1, but not of NOX2 or NOX4. The production of nitric oxide by LSECs was significantly attenuated by PA-treatment in WT but not in Nox1KO. When the in vitro relaxation of TWNT1, a cell line that originated from hepatic stellate cells, was assessed by the gel contraction assay, the relaxation of stellate cells induced by LSECs was attenuated by PA treatment. In contrast, the relaxation effect of LSECs was preserved in cells isolated from Nox1KO. Taken together, the up-regulation of NOX1 in LSECs may elicit peroxynitrite-mediated cellular injury and impaired hepatic microcirculation through the reduced bioavailability of nitric oxide. ROS derived from NOX1 may therefore constitute a critical component in the progression of NAFLD.
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影响因子：
2.4
作者：
Nozaki Y;Fujita K;Wada K;Yoneda M;Kessoku T;Shinohara Y;Imajo K;Ogawa Y;Nakamuta M;Saito S;Masaki N;Nagashima Y;Terauchi Y;Nakajima A
通讯作者：
Nakajima A
影响因子：
15.9
作者：
Leclercq, IA;Farrell, GC;Robertson, GR
通讯作者：
Robertson, GR
影响因子：
25.7
作者：
Leung, Tung-Ming;Nieto, Natalia
通讯作者：
Nieto, Natalia
影响因子：
5
作者：
Francque, Sven;Laleman, Wim;Michielsen, Peter
通讯作者：
Michielsen, Peter
影响因子：
13.8
作者：
Iwakiri Y;Kim MY
通讯作者：
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