Caspase-1 as a central regulator of high fat diet-induced non-alcoholic steatohepatitis.
Caspase-1 as a central regulator of high fat diet-induced non-alcoholic steatohepatitis.
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DOI：
10.1371/journal.pone.0056100
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Nagy LE
中科院分区：
文献类型：
--
作者：
Dixon LJ;Flask CA;Papouchado BG;Feldstein AE;Nagy LE
非酒精性脂肪性肝炎（NASH）与caspase激活有关。然而，促炎性半胱天冬酶或炎性小体在饮食诱导的肝损伤中的作用尚未研究。我们的目的是研究caspase-1在高脂诱导的NASH中的作用。将C57 BL/6野生型和半胱天冬酶1敲除（Casp 1-/-）小鼠置于12周高脂肪饮食中。高脂饮食的野生型小鼠增加了肝脏caspase-1和IL-1β的表达。高脂肪饮食的野生型和Casp 1-/-小鼠比对照饮食的小鼠体重增加更多。在高脂饮食的野生型小鼠中，肝脏脂肪变性和TG水平增加，但在不存在半胱天冬酶-1的情况下减弱。血浆胆固醇和游离脂肪酸升高野生型，但不是Casp 1-/-小鼠，高脂肪饮食。与对照组相比，野生型和高脂肪饮食的Casp 1-/-小鼠的ALT水平均升高。与高脂饮食的野生型小鼠相比，高脂饮食的Casp 1-/-小鼠中与脂肪生成相关的基因的肝脏mRNA表达较低，而与脂肪酸氧化相关的基因不受饮食或基因型的影响。高脂饮食野生型小鼠肝脏TNFα和Mcp-1 mRNA表达增加，而高脂饮食Casp 1-/-小鼠肝脏TNFα和Mcp-1 mRNA表达无明显变化。与对照组相比，高脂饮食野生型小鼠中αSMA阳性细胞、天狼星红染色和Col 1 α1 mRNA增加。caspase-1的缺乏阻止了这些增加。总之，半胱天冬酶-1的缺乏改善了高脂肪饮食诱导的肥胖对肝脏的损伤作用。具体而言，caspase-1缺陷的小鼠受到保护，免于高脂肪诱导的肝脂肪变性、炎症和早期纤维化。这些数据表明炎性小体是NASH的重要治疗靶点。
Nonalcoholic steatohepatitis (NASH) is associated with caspase activation. However, a role for pro-inflammatory caspases or inflammasomes has not been explored in diet-induced liver injury. Our aims were to examine the role of caspase-1 in high fat-induced NASH. C57BL/6 wild-type and caspase 1-knockout (Casp1-/-) mice were placed on a 12-week high fat diet. Wild-type mice on the high fat diet increased hepatic expression of pro-caspase-1 and IL-1β. Both wild-type and Casp1-/- mice on the high fat diet gained more weight than mice on a control diet. Hepatic steatosis and TG levels were increased in wild-type mice on high fat diet, but were attenuated in the absence of caspase-1. Plasma cholesterol and free fatty acids were elevated in wild-type, but not Casp1-/- mice, on high fat diet. ALT levels were elevated in both wild-type and Casp1-/- mice on high fat diet compared to control. Hepatic mRNA expression for genes associated with lipogenesis was lower in Casp1-/- mice on high fat diet compared to wild-type mice on high fat diet, while genes associated with fatty acid oxidation were not affected by diet or genotype. Hepatic Tnfα and Mcp-1 mRNA expression was increased in wild-type mice on high fat diet, but not in Casp1-/- mice on high fat diet. αSMA positive cells, Sirius red staining, and Col1α1 mRNA were increased in wild-type mice on high fat diet compared to control. Deficiency of caspase-1 prevented those increases. In summary, the absence of caspase-1 ameliorates the injurious effects of high fat diet-induced obesity on the liver. Specifically, mice deficient in caspase-1 are protected from high fat-induced hepatic steatosis, inflammation and early fibrogenesis. These data point to the inflammasome as an important therapeutic target for NASH.
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影响因子：
29.4
作者：
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