Lytle Kelli A, Wong Carmen P, Jump Donald B
Nutrition Program, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon, United States of America.
Linus Pauling Institute, Oregon State University, Corvallis, Oregon, United States of America.
PLoS One. 2017 Apr 19;12(4):e0173376. doi: 10.1371/journal.pone.0173376. eCollection 2017.
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.
非酒精性脂肪性肝病（NAFLD）是西方社会主要的公共卫生问题。非酒精性脂肪性肝炎（NASH）是NAFLD的进展形式，其特征为肝脂肪变性、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。尽管公众对其日益关注，但美国食品药品监督管理局（FDA）仍未批准任何NASH治疗方法。在一项前期研究中，我们使用Ldlr-/-小鼠作为西方饮食（WD）诱导的NASH临床前模型，发现膳食补充二十二碳六烯酸（DHA，22:6,ω3）可减轻WD诱导的NASH。在此，我们评估了在WD和低脂饮食中补充DHA对已患疾病小鼠的NASH进行完全逆转的能力。
喂食WD 22周的Ldlr-/-小鼠出现代谢综合征（MetS）和严重的NASH表型，包括肥胖、血脂异常、高血糖、肝脂肪变性、炎症、纤维化和肝脏多不饱和脂肪酸（PUFA）含量降低。这些小鼠被随机分为5组：一个基线组（WDB，在22周时处死）和4种处理组：1）WD + 橄榄油（WDO）；2）WD + DHA（WDD）；3）恢复正常饮食 + 橄榄油（WDChO）；或4）恢复正常饮食 + DHA（WDChD）。四个处理组在各自的饮食条件下维持8周。另外一组在整个30周的研究期间维持标准实验室饲料（参考饮食，RD）喂养。
与WDB组相比，WDO组肝脏中与炎症相关基因（Opn、Il1rn、Gdf15）的表达增加，肝脏纤维化（胶原染色、Col1A1、Thbs2、Lox）增加，反映疾病进展。相比之下，WDD组小鼠肝脏中C20 - 22 ω3 PUFA增加，且无NASH进展的迹象。WDChO或WDChD组的MetS和NASH标志物显著减轻，与RD组略有差异，反映疾病缓解。
虽然这些研究表明在WD中补充DHA可阻止WD诱导的NASH进展，但单独使用DHA并不能促进饮食诱导的MetS或NASH完全缓解。
