Docosahexaenoic Acid Attenuates Hepatic Inflammation, Oxidative Stress, and Fibrosis without Decreasing Hepatosteatosis in a Ldlr-/- Mouse Model of Western Diet-Induced Nonalcoholic Steatohepatitis
Docosahexaenoic Acid Attenuates Hepatic Inflammation, Oxidative Stress, and Fibrosis without Decreasing Hepatosteatosis in a Ldlr-/- Mouse Model of Western Diet-Induced Nonalcoholic Steatohepatitis
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DOI：
10.3945/jn.112.171322
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发表时间：
2013-03-01
影响因子：
4.2
通讯作者：
Jump, Donald B.
中科院分区：
文献类型：
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作者：
Depner, Christopher M.;Philbrick, Kenneth A.;Jump, Donald B.
非酒精性脂肪性肝病（NAFLD）和非酒精性脂肪性肝炎（NASH）的发病率与肥胖的发病率平行增加。虽然NAFLD和NASH都以脂肪肝为特征，但NASH以肝损伤、炎症、氧化应激和纤维化为特征。我们以前报道过，给Ldlr（-/-）小鼠喂食含有鲱鱼油的高脂肪、高胆固醇饮食，可以减弱NASH的几个标志物，包括脂肪肝、炎症和纤维化。在此，我们检验了DHA [22：6（n-3）]在预防Ldlr（-/-）小鼠中西方饮食（WD）诱导的NASH方面比EPA [20：5（n-3）]更有效的假设。给小鼠喂食补充有橄榄油（OO）、EPA、DHA或EPA + DHA的WD 16周。WD + OO喂养诱导了严重的NASH表型，其特征在于强烈的肝脂肪变性、炎症、氧化应激和纤维化。尽管C20-22（n-3）脂肪酸处理均未预防WD诱导的肝脂肪变性，但所有3种（n-3）含PUFA的饮食均显著减弱了WD诱导的炎症、纤维化和肝损伤。膳食DHA抑制炎症（Clec 4F、F4/80、Trl 4、Trl 9、CD 14、Myd 88）、纤维化（Procol 1 α 1、Tgf β 1）和氧化应激（NADPH氧化酶亚基Nox 2、p22 phox、p40 phox、p47 phox、p67 phox）的肝脏标志物的能力显著大于膳食EPA。DHA对这些标志物的影响包括DHA介导的肝Fads 1 mRNA丰度和肝花生四烯酸含量的抑制。因为DHA抑制NASH标志物不需要减少脂肪肝，膳食DHA可能有助于对抗肥胖人群的NASH。J.营养143：315-323，2013.
The incidence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) has increased in parallel with the incidence of obesity. While both NAFLD and NASH are characterized by hepatosteatosis, NASH is characterized by hepatic damage, inflammation, oxidative stress, and fibrosis. We previously reported that feeding Ldlr(-/-) mice a high-fat, high-cholesterol diet containing menhaden oil attenuated several markers of NASH, including hepatosteatosis, inflammation, and fibrosis. Herein, we test the hypothesis that DHA [22:6 (n-3)] is more effective than EPA [20:5 (n-3)] at preventing Western diet (WD)-induced NASH in Ldlr(-/-) mice. Mice were fed the WD supplemented with either olive oil (OO), EPA, DHA, or EPA + DHA for 16 wk. WD + OO feeding induced a severe NASH phenotype, characterized by robust hepatosteatosis, inflammation, oxidative stress, and fibrosis. Whereas none of the C20-22 (n-3) fatty acid treatments prevented WD-induced hepatosteatosis, all 3 (n-3) PUFA-containing diets significantly attenuated WD-induced inflammation, fibrosis, and hepatic damage. The capacity of dietary DHA to suppress hepatic markers of inflammation (Clec4F, F4/80, Trl4, Trl9, CD14, Myd88), fibrosis (Procol1 alpha 1, Tgf beta 1), and oxidative stress (NADPH oxidase subunits Nox2, p22phox, p40phox, p47phox, p67phox) was significantly greater than dietary EPA. The effects of DHA on these markers paralleled DHA-mediated suppression of hepatic Fads1 mRNA abundance and hepatic arachidonic acid content. Because DHA suppression of NASH markers does not require a reduction in hepatosteatosis, dietary DHA may be useful in combating NASH in obese humans. J. Nutr. 143: 315-323, 2013.