Deficiency of eNOS exacerbates early-stage NAFLD pathogenesis by changing the fat distribution.
Deficiency of eNOS exacerbates early-stage NAFLD pathogenesis by changing the fat distribution.
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DOI：
10.1186/s12876-015-0409-9
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发表时间：
2015-12-17
影响因子：
2.4
通讯作者：
Nakajima A
中科院分区：
文献类型：
--
作者：
Nozaki Y;Fujita K;Wada K;Yoneda M;Shinohara Y;Imajo K;Ogawa Y;Kessoku T;Nakamuta M;Saito S;Masaki N;Nagashima Y;Terauchi Y;Nakajima A
尽管已经报道了许多与非酒精性脂肪性肝病（NAFLD）/非酒精性脂肪性肝炎（NASH）密切相关的因子和分子，但内皮型一氧化氮合酶（eNOS）衍生的一氧化氮（NO）在NAFLD/NASH发病机制中的作用仍不清楚。因此，我们研究了eNOS衍生的NO在NAFLD发病机制中的作用，使用系统性eNOS敲除小鼠喂养高脂肪饮食。eNOS基因敲除小鼠和野生型小鼠喂食基础饮食或高脂肪饮食12周。评估肝脏中的脂质积聚和炎症，并分析与NAFLD/NASH和肝组织血流密切相关的各种因素。与野生型小鼠相比，在喂食高脂饮食12周后，eNOS敲除小鼠的肝脏中脂质积累和炎症更广泛，内脏脂肪组织中脂质积累不那么广泛。虽然eNOS敲除小鼠和喂食高脂饮食的野生型小鼠之间的全身胰岛素抵抗相当，但与喂食高脂饮食的野生型小鼠相比，eNOS敲除小鼠的肝组织血流明显受到抑制。与野生型小鼠相比，在喂食高脂饮食的小鼠中，eNOS敲除小鼠的微粒体甘油三酯转移蛋白活性下调。eNOS衍生的NO的缺乏可能通过调节肝组织血流改变小鼠模型中的脂肪分布而加剧NASH发病机制的早期阶段。
Although many factors and molecules that are closely associated with non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) have been reported, the role of endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO) in the pathogenesis of NAFLD/NASH remains unclear. We therefore investigated the role of eNOS-derived NO in NAFLD pathogenesis using systemic eNOS-knockout mice fed a high-fat diet. eNOS-knockout and wild-type mice were fed a basal diet or a high-fat diet for 12 weeks. Lipid accumulation and inflammation were evaluated in the liver, and various factors that are closely associated with NAFLD/NASH and hepatic tissue blood flow were analyzed. Lipid accumulation and inflammation were more extensive in the liver and lipid accumulation was less extensive in the visceral fat tissue in eNOS-knockout mice, compared with wild-type mice, after 12 weeks of being fed a high-fat diet. While systemic insulin resistance was comparable between the eNOS-knockout and wild-type mice fed a high-fat diet, hepatic tissue blood flow was significantly suppressed in the eNOS-knockout mice, compared with the wild-type mice, in mice fed a high-fat diet. The microsomal triglyceride transfer protein activity was down-regulated in eNOS-knockout mice, compared with wild-type mice, in mice fed a high-fat diet. A deficiency of eNOS-derived NO may exacerbate the early-stage of NASH pathogenesis by changing the fat distribution in a mouse model via the regulation of hepatic tissue blood flow.