Is Western Diet-Induced Nonalcoholic Steatohepatitis in Ldlr-/- Mice Reversible?
Is Western Diet-Induced Nonalcoholic Steatohepatitis in Ldlr-/- Mice Reversible?
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DOI：
10.1371/journal.pone.0146942
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发表时间：
2016-01-13
期刊：
影响因子：
3.7
通讯作者：
Jump, Donald B.
中科院分区：
文献类型：
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作者：
Lytle, Kelli A.;Jump, Donald B.
背景非酒精性脂肪性肝病(NAFLD)是西方社会的主要公共卫生负担。进展型非酒精性脂肪性肝炎(NASH)的特征是肝脏骨质疏松症、炎症、氧化应激和肝损伤，可进展为纤维化和肝硬化；这些都是肝细胞癌的危险因素。考虑到NASH的范围，验证治疗方案(即低脂饮食和减肥)是当务之急。方法我们评估了两种饮食，非纯饲料(NP)和纯净(低脂低胆固醇，LFLC)饮食对逆转西方饮食(WD)诱导的Ldlr(-/-)小鼠NASH和纤维化的效果。结果喂食WD 22-24周的小鼠出现了严重的肝纤维化，而喂食WD的小鼠多饲养7-8周，出现中度纤维化的NASH。以NP或LFLC饲料喂养的WD小鼠显著降低了体重和代谢综合征(血脂异常、高血糖)的血浆标记物，以及炎症(Mcp1)、氧化应激(NOX2)、纤维化(Col1a、LOXL2、TIMP1)和胶原交联物(羟脯氨酸)的肝脏基因表达标记物。时间进程分析表明，从WD饮食转变为LFLC饮食后，血浆甘油三酯和肝脏Col1A1 mRNA迅速下降。然而，在改变LFLC饮食8周后，肝脏甘油三酯含量和肝纤维化并未恢复到正常水平。时程研究进一步揭示了血浆炎症标记物(TLR2激活物)和肝纤维化标记物(COL1A、TIMP1、LOXL2)之间的强烈关联(r(2)>；=0.52)。炎症和纤维化标志物与饮食诱导的肝脏omega 3和omega 6多不饱和脂肪酸(PUFA)含量的变化呈负相关(r(2)>；=0.32)。结论这些研究建立了血浆炎症标志物和肝脏PUFA和纤维化之间的时间联系。低脂低胆固醇饮食促进WD诱导的NASH和Ldlr(-/-)小鼠的许多(但不是全部)特征的逆转。
BackgroundNonalcoholic fatty liver disease (NAFLD) is a major public health burden in western societies. The progressive form of NAFLD, nonalcoholic steatohepatitis (NASH), is characterized by hepatosteatosis, inflammation, oxidative stress, and hepatic damage that can progress to fibrosis and cirrhosis; risk factors for hepatocellular carcinoma. Given the scope of NASH, validating treatment protocols (i.e., low fat diets and weight loss) is imperative.MethodsWe evaluated the efficacy of two diets, a non-purified chow (NP) and purified (low-fat low-cholesterol, LFLC) diet to reverse western diet (WD)-induced NASH and fibrosis in Ldlr(-/-) mice.ResultsMice fed WD for 22-24 weeks developed robust hepatosteatosis with mild fibrosis, while mice maintained on the WD an additional 7-8 weeks developed NASH with moderate fibrosis. Returning WD-fed mice to the NP or LFLC diets significantly reduced body weight and plasma markers of metabolic syndrome (dyslipidemia, hyperglycemia) and hepatic gene expression markers of inflammation (Mcp1), oxidative stress (Nox2), fibrosis (Col1A, LoxL2, Timp1) and collagen crosslinking (hydroxyproline). Time course analyses established that plasma triglycerides and hepatic Col1A1 mRNA were rapidly reduced following the switch from the WD to the LFLC diet. However, hepatic triglyceride content and fibrosis did not return to normal levels 8 weeks after the change to the LFLC diet. Time course studies further revealed a strong association (r(2) >= 0.52) between plasma markers of inflammation (TLR2 activators) and hepatic fibrosis markers (Col1A, Timp1, LoxL2). Inflammation and fibrosis markers were inversely associated (r(2) >= 0.32) with diet-induced changes in hepatic omega 3 and omega 6 polyunsaturated fatty acids (PUFA) content.ConclusionThese studies establish a temporal link between plasma markers of inflammation and hepatic PUFA and fibrosis. Low-fat low-cholesterol diets promote reversal of many, but not all, features associated with WD-induced NASH and fibrosis in Ldlr(-/-) mice.