Eicosapentaenoic acid ameliorates non-alcoholic steatohepatitis in a novel mouse model using melanocortin 4 receptor-deficient mice.
Eicosapentaenoic acid ameliorates non-alcoholic steatohepatitis in a novel mouse model using melanocortin 4 receptor-deficient mice.
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DOI：
10.1371/journal.pone.0121528
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Ogawa Y
中科院分区：
文献类型：
--
作者：
Konuma K;Itoh M;Suganami T;Kanai S;Nakagawa N;Sakai T;Kawano H;Hara M;Kojima S;Izumi Y;Ogawa Y
人们尝试寻找治疗非酒精性脂肪性肝炎（NASH）的新策略，但其临床疗效尚不清楚。我们最近报道了一种新的NASH啮齿动物模型，使用黑皮质素4受体缺陷（MC 4 R-KO）小鼠，其表现出的事件序列包括肝脂肪变性，肝纤维化和肝细胞癌与肥胖相关的表型。在MC 4 R-KO小鼠的肝脏中，存在称为肝冠状结构（hCLS）的独特组织学特征，其中巨噬细胞与死肝细胞和纤维化细胞相互作用，从而加速炎症和纤维化。在这项研究中，我们采用MC 4 R-KO小鼠来检查高度纯化的二十碳五烯酸（EPA）（一种临床上可用的n-3多不饱和脂肪酸）对NASH发展的影响。EPA处理显著防止肝细胞损伤、hCLS形成和肝纤维化沿着脂质积聚的发展。EPA治疗即使在MC 4 R-KO小鼠发生NASH后也有效。有趣的是，肝纤维化的改善伴随着hCLS形成和血浆激肽释放酶介导的转化生长因子-β活化的减少。此外，EPA治疗增加了脂联素的血清浓度，脂联素是一种具有抗炎和抗纤维化特性的脂肪细胞因子。总的来说，EPA治疗有效地预防了MC 4 R-KO小鼠中NASH的发展和进展，沿着肝脂肪变性的改善。这项研究揭示了EPA的一种新的抗纤维化机制，从而提出了治疗NASH的临床意义。
Many attempts have been made to find novel therapeutic strategies for non-alcoholic steatohepatitis (NASH), while their clinical efficacy is unclear. We have recently reported a novel rodent model of NASH using melanocortin 4 receptor-deficient (MC4R-KO) mice, which exhibit the sequence of events that comprise hepatic steatosis, liver fibrosis, and hepatocellular carcinoma with obesity-related phenotypes. In the liver of MC4R-KO mice, there is a unique histological feature termed hepatic crown-like structures (hCLS), where macrophages interact with dead hepatocytes and fibrogenic cells, thereby accelerating inflammation and fibrosis. In this study, we employed MC4R-KO mice to examine the effect of highly purified eicosapentaenoic acid (EPA), a clinically available n-3 polyunsaturated fatty acid, on the development of NASH. EPA treatment markedly prevented the development of hepatocyte injury, hCLS formation and liver fibrosis along with lipid accumulation. EPA treatment was also effective even after MC4R-KO mice developed NASH. Intriguingly, improvement of liver fibrosis was accompanied by the reduction of hCLS formation and plasma kallikrein-mediated transforming growth factor-β activation. Moreover, EPA treatment increased the otherwise reduced serum concentrations of adiponectin, an adipocytokine with anti-inflammatory and anti-fibrotic properties. Collectively, EPA treatment effectively prevents the development and progression of NASH in MC4R-KO mice along with amelioration of hepatic steatosis. This study unravels a novel anti-fibrotic mechanism of EPA, thereby suggesting a clinical implication for the treatment of NASH.
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DOI：
10.1002/cne.22221
发表时间：
2010-01-01
期刊：
The Journal of comparative neurology
影响因子：
--
作者：
Gautron L;Lee C;Funahashi H;Friedman J;Lee S;Elmquist J
通讯作者：
Elmquist J
影响因子：
8.2
作者：
Flachs, P;Mohamed-Ali, V;Kopecky, J
通讯作者：
Kopecky, J
影响因子：
29.4
作者：
Day, CP
通讯作者：
Day, CP
DOI：
10.1161/atvbaha.106.136853
发表时间：
2007-09-01
影响因子：
8.7
作者：
Itoh, Michiko;Suganami, Takayoshi;Ogawa, Yoshihiro
通讯作者：
Ogawa, Yoshihiro
影响因子：
25.7
作者：
Ishii, Hajime;Horie, Yasuo;Ohnishi, Hirohide
通讯作者：
Ohnishi, Hirohide