Docosahexaenoic acid blocks progression of western diet-induced nonalcoholic steatohepatitis in obese Ldlr-/- mice.
Docosahexaenoic acid blocks progression of western diet-induced nonalcoholic steatohepatitis in obese Ldlr-/- mice.
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DOI：
10.1371/journal.pone.0173376
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Jump DB
中科院分区：
文献类型：
--
作者：
Lytle KA;Wong CP;Jump DB
非酒精性脂肪性肝病（NAFLD）是西方社会的主要公共卫生问题。非酒精性脂肪性肝炎（NASH）是NAFLD的进展形式，其特征在于肝脂肪变性、炎症、氧化应激和纤维化。NASH是肝硬化和肝细胞癌的危险因素。预计到2020年，NASH将成为肝移植的主要原因。尽管这种日益增长的公共卫生问题，仍然没有食品和药物管理局（FDA）批准的NASH治疗。使用Ldlr -/-小鼠作为西方饮食（WD）诱导的NASH的临床前模型，我们先前在预防研究中确定了饮食补充二十二碳六烯酸（DHA，22：6，ω3）减弱WD诱导的NASH。在此，我们评估了WD的DHA补充和低脂饮食完全逆转具有预先存在的疾病的小鼠中的NASH的能力。喂食WD 22周的Ldlr -/-小鼠出现代谢综合征（MetS）和严重NASH表型，包括肥胖、血脂异常、高血糖、肝脂肪变性、炎症、纤维化和低肝多不饱和脂肪酸（PUFA）含量。将这些小鼠随机分为5组：基线组（WDB，在22周时处死）和4种治疗：1）WD +橄榄油（WDO）; 2）WD + DHA（WDD）; 3）恢复食物+橄榄油（WDChO）;或4）恢复食物+ DHA（WDChD）。四个处理组维持其各自的饮食8周。另外一组在30周的研究期间维持标准实验室食物（参考饮食，RD）。与WDB组相比，WDO组显示与炎症（Opn、Il 1 rn、Gdf 15）、肝纤维化（胶原染色、Col 1A 1、Thbs 2、Lox）相关的基因的肝表达增加，反映疾病进展。相比之下，WDD组小鼠的肝脏C20-22 ω3 PUFA增加，没有NASH进展的证据。WDChO或WDChD组中的MetS和NASH标志物显著减弱，并且与RD组略有不同，反映了疾病缓解。虽然这些研究确定了WD的DHA补充阻断了WD诱导的NASH进展，但单独的DHA并不能促进饮食诱导的MetS或NASH的完全缓解。
Nonalcoholic fatty liver disease (NAFLD) is a major public health concern in western societies. Nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD, is characterized by hepatic steatosis, inflammation, oxidative stress and fibrosis. NASH is a risk factor for cirrhosis and hepatocellular carcinoma. NASH is predicted to be the leading cause of liver transplants by 2020. Despite this growing public health concern, there remain no Food and Drug Administration (FDA) approved NASH treatments. Using Ldlr -/- mice as a preclinical model of western diet (WD)-induced NASH, we previously established that dietary supplementation with docosahexaenoic acid (DHA, 22:6,ω3) attenuated WD-induced NASH in a prevention study. Herein, we evaluated the capacity of DHA supplementation of the WD and a low fat diet to fully reverse NASH in mice with pre-existing disease. Ldlr -/- mice fed the WD for 22 wks developed metabolic syndrome (MetS) and a severe NASH phenotype, including obesity, dyslipidemia, hyperglycemia, hepatic steatosis, inflammation, fibrosis and low hepatic polyunsaturated fatty acid (PUFA) content. These mice were randomized to 5 groups: a baseline group (WDB, sacrificed at 22 wks) and 4 treatments: 1) WD + olive oil (WDO); 2) WD + DHA (WDD); 3) returned to chow + olive oil (WDChO); or 4) returned to chow + DHA (WDChD). The four treatment groups were maintained on their respective diets for 8 wks. An additional group was maintained on standard laboratory chow (Reference Diet, RD) for the 30-wk duration of the study. When compared to the WDB group, the WDO group displayed increased hepatic expression of genes linked to inflammation (Opn, Il1rn, Gdf15), hepatic fibrosis (collagen staining, Col1A1, Thbs2, Lox) reflecting disease progression. Mice in the WDD group, in contrast, had increased hepatic C20-22 ω3 PUFA and no evidence of NASH progression. MetS and NASH markers in the WDChO or WDChD groups were significantly attenuated and marginally different from the RD group, reflecting disease remission. While these studies establish that DHA supplementation of the WD blocks WD-induced NASH progression, DHA alone does not promote full remission of diet-induced MetS or NASH.