Liver microRNA-21 is overexpressed in non-alcoholic steatohepatitis and contributes to the disease in experimental models by inhibiting PPARα expression.
Liver microRNA-21 is overexpressed in non-alcoholic steatohepatitis and contributes to the disease in experimental models by inhibiting PPARα expression.
复制标题
DOI：
10.1136/gutjnl-2014-308883
复制
发表时间：
2016-11
期刊：
影响因子：
24.5
通讯作者：
Rautou PE
中科院分区：
文献类型：
--
作者：
Loyer X;Paradis V;Hénique C;Vion AC;Colnot N;Guerin CL;Devue C;On S;Scetbun J;Romain M;Paul JL;Rothenberg ME;Marcellin P;Durand F;Bedossa P;Prip-Buus C;Baugé E;Staels B;Boulanger CM;Tedgui A;Rautou PE
先前的研究表明，microRNA-21可能在非酒精性脂肪性肝炎（NASH）的肝脏中上调，但其在这种疾病发展中的作用仍然未知。本研究旨在确定microRNA-21在NASH中的作用。我们在不同的NASH小鼠模型中抑制或抑制microRNA-21：（a）喂食高脂饮食并接受Escheromir-21或Escheromir对照治疗的低密度脂蛋白受体缺陷（Ldlr−/−）小鼠;（B）喂食甲硫氨酸胆碱缺陷（MCD）饮食的microRNA-21缺陷和野生型小鼠;（c）喂食MCD饲料并接受Escheromir-21或Escheromir对照给药的过氧化物酶体增殖激活剂受体α（PPARα）缺陷小鼠。我们评估了NASH的特征，并确定了肝脏microRNA-21水平和细胞定位。还定量了NASH、轻度脂肪变性或正常肝脏患者肝脏中的MicroRNA-21水平，并确定了定位。在喂食高脂饲料的Ldlr−/−和喂食MCD饲料的野生型小鼠中，抑制或抑制肝脏microRNA-21表达可减少肝细胞损伤、炎症和纤维化，而不影响肝脏脂质蓄积。在小鼠模型以及NASH患者中，肝脏microRNA-21主要在胆管和炎症细胞中过表达，但在轻度脂肪变性患者中则没有。PPARα是一种已知的microRNA-21靶标，与NASH有关，在NASH小鼠的肝脏中减少，并在microRNA-21抑制或抑制后恢复。在PPARα缺陷小鼠中，Escheromir-21的作用丧失。MicroRNA-21抑制或抑制通过恢复PPARα表达来减少肝损伤、炎症和纤维化。Antagomir-21可能是NASH未来的治疗策略。
Previous studies suggested that microRNA-21 may be upregulated in the liver in non-alcoholic steatohepatitis (NASH), but its role in the development of this disease remains unknown. This study aimed to determine the role of microRNA-21 in NASH. We inhibited or suppressed microRNA-21 in different mouse models of NASH: (a) low-density lipoprotein receptor-deficient (Ldlr−/−) mice fed a high-fat diet and treated with antagomir-21 or antagomir control; (b) microRNA-21-deficient and wild-type mice fed a methionine-choline-deficient (MCD) diet; (c) peroxisome proliferation-activator receptor α (PPARα)-deficient mice fed an MCD diet and treated with antagomir-21 or antagomir control. We assessed features of NASH and determined liver microRNA-21 levels and cell localisation. MicroRNA-21 levels were also quantified in the liver of patients with NASH, bland steatosis or normal liver and localisation was determined. Inhibiting or suppressing liver microRNA-21 expression reduced liver cell injury, inflammation and fibrogenesis without affecting liver lipid accumulation in Ldlr−/− fed a high-fat diet and in wild-type mice fed an MCD diet. Liver microRNA-21 was overexpressed, primarily in biliary and inflammatory cells, in mouse models as well as in patients with NASH, but not in patients with bland steatosis. PPARα, a known microRNA-21 target, implicated in NASH, was decreased in the liver of mice with NASH and restored following microRNA-21 inhibition or suppression. The effect of antagomir-21 was lost in PPARα-deficient mice. MicroRNA-21 inhibition or suppression decreases liver injury, inflammation and fibrosis, by restoring PPARα expression. Antagomir-21 might be a future therapeutic strategy for NASH.
登录
查看更多内容
DOI：
10.4049/jimmunol.0803560
发表时间：
2009-04-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Lu TX;Munitz A;Rothenberg ME
通讯作者：
Rothenberg ME
DOI：
10.4049/jimmunol.1101235
发表时间：
2011-09-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Lu TX;Hartner J;Lim EJ;Fabry V;Mingler MK;Cole ET;Orkin SH;Aronow BJ;Rothenberg ME
通讯作者：
Rothenberg ME
影响因子：
25.7
作者：
Kakisaka, Keisuke;Cazanave, Sophie C.;Werneburg, Nathan W.;Razumilava, Nataliya;Mertens, Joachim C.;Bronk, Steve F.;Gores, Gregory J.
通讯作者：
Gores, Gregory J.
影响因子：
20.1
作者：
Loyer, Xavier;Potteaux, Stephane;Tedgui, Alain
通讯作者：
Tedgui, Alain
影响因子：
4.3
作者：
Brunt, Elizabeth M.;Tiniakos, Dina G.
通讯作者：
Tiniakos, Dina G.