Inhibition of soluble epoxide hydrolase attenuates high-fat-diet-induced hepatic steatosis by reduced systemic inflammatory status in mice.
Inhibition of soluble epoxide hydrolase attenuates high-fat-diet-induced hepatic steatosis by reduced systemic inflammatory status in mice.
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DOI：
10.1371/journal.pone.0039165
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Zhu Y
中科院分区：
文献类型：
--
作者：
Liu Y;Dang H;Li D;Pang W;Hammock BD;Zhu Y
非酒精性脂肪肝与肥胖有关，被认为是一种炎症性疾病。可溶性环氧化物水解酶 (sEH) 是水解环氧二十碳三烯酸的主要酶，可减弱其心血管保护和抗炎作用。我们研究了 sEH 抑制是否可以预防高脂 (HF) 饮食诱导的小鼠脂肪肝及其潜在机制。与野生型同窝小鼠相比，sEH 缺失小鼠表现出较低的饮食诱导的肝脏脂质积累，如油红 O 染色和甘油三酯水平所示。我们通过给 C57BL/6 小鼠喂食 HF 饮食 8 周（短期）或 16 周（长期）并施用选择性 sEH 抑制剂 t-AUCB，研究了 sEH 抑制对饮食诱导的脂肪肝的影响。 sEH 抑制对 HF 饮食增加的身体和脂肪组织重量或糖耐量受损没有影响，但减轻了饮食诱导的肝脂肪变性。腺病毒介导的肝脏中 sEH 的过度表达增加了肝脏中甘油三酯的水平和肝脏炎症反应。令人惊讶的是，肝脏中 sEH 的诱导表达仅在长期 HF 饮食中发生，而不是短期 HF 饮食，这表明 HF 饮食对调节 sEH 表达具有二次效应。此外，sEH 抑制减弱了 HF 饮食诱导的血浆促炎细胞因子水平的增加及其在脂肪组织中 mRNA 的上调，同时伴随着巨噬细胞浸润的增加。因此，抑制sEH可以减轻HF饮食引起的肝脏脂肪变性，这可能与其对脂肪组织的抗炎作用和对肝脏的直接抑制作用有关。 sEH 可能是高频饮食诱导的肝脂肪变性抑制全身炎症的治疗靶点。
Non-alcoholic fatty liver disease is associated with obesity and considered an inflammatory disease. Soluble epoxide hydrolase (sEH) is a major enzyme hydrolyzing epoxyeicosatrienoic acids and attenuates their cardiovascular protective and anti-inflammatory effects. We examined whether sEH inhibition can protect against high-fat (HF)-diet–induced fatty liver in mice and the underlying mechanism. Compared with wild-type littermates, sEH-null mice showed lower diet-induced lipid accumulation in liver, as seen by Oil-red O staining and triglycerides levels. We studied the effect of sEH inhibition on diet-induced fatty liver by feeding C57BL/6 mice an HF diet for 8 weeks (short-term) or 16 weeks (long-term) and administering t-AUCB, a selective sEH inhibitor. sEH inhibition had no effect on the HF-diet–increased body and adipose tissue weight or impaired glucose tolerance but alleviated the diet-induced hepatic steatosis. Adenovirus-mediated overexpression of sEH in liver increased the level of triglycerides in liver and the hepatic inflammatory response. Surprisingly, the induced expression of sEH in liver occurred only with the long-term but not short-term HF diet, which suggests a secondary effect of HF diet on regulating sEH expression. Furthermore, sEH inhibition attenuated the HF-diet–induced increase in plasma levels of proinflammatory cytokines and their mRNA upregulation in adipose tissue, which was accompanied by increased macrophage infiltration. Therefore, sEH inhibition could alleviate HF-diet–induced hepatic steatosis, which might involve its anti-inflammatory effect in adipose tissue and direct inhibition in liver. sEH may be a therapeutic target for HF-diet–induced hepatic steatosis in inhibiting systemic inflammation.
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影响因子：
5
作者：
Deng Y;Theken KN;Lee CR
通讯作者：
Lee CR
影响因子：
--
作者：
Iyer A;Kauter K;Alam MA;Hwang SH;Morisseau C;Hammock BD;Brown L
通讯作者：
Brown L
DOI：
10.1073/pnas.1011278107
发表时间：
2010-09-28
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
7.7
作者：
Lee YS;Li P;Huh JY;Hwang IJ;Lu M;Kim JI;Ham M;Talukdar S;Chen A;Lu WJ;Bandyopadhyay GK;Schwendener R;Olefsky J;Kim JB
通讯作者：
Kim JB
影响因子：
6.7
作者：
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通讯作者：
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