Long-chain (n-3) PUFA and non-alcoholic fatty liver disease Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/vd66w4569

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  • Non-alcoholic fatty liver disease (NAFLD) is defined as excess hepatic lipid accumulation, in the absence of excess alcohol consumption and chronic liver disease. NAFLD can range in severity from simple fatty liver (steatosis) to non-alcoholic steatohepatitis (NASH). NASH is defined as hepatic steatosis with inflammation and hepatic injury and describes the progressive form of NAFLD. NASH promotes development of hepatic fibrosis, cirrhosis, advanced liver disease, and potentially increases risk of hepatocellular carcinoma. The incidence of NAFLD has increased in parallel with that of obesity. It is estimated that by the year 2020 NAFLD will be the leading cause of liver transplants in the United States. The current standard of care for patients diagnosed with NAFLD/NASH is to treat for liver disease and the associated co-morbidities including obesity, Type 2 Diabetes Mellitus (T2D), hyperlipidemia, and the metabolic syndrome. There are no treatments specific to NAFLD or NASH. As such, new treatment modalities and an improved understanding of NAFLD are urgently needed to address this impending public health burden. 20-22 carbon (C20-22) (n-3) polyunsaturated fatty acids (PUFA) have well established anti-inflammatory properties and many known benefits on hepatic lipid metabolism, and thus are attractive agents to potentially combat NAFLD/NASH in humans. As such, my overall goal was to establish the therapeutic efficacy of (n-3) PUFA supplementation as a treatment modality for NAFLD/NASH. First, I assessed several mouse models of NAFLD as follows: high-fat (HF; 60% calories as fat), high fat-high cholesterol (HFHC; 54.4% fat, 0.5% cholesterol), and the western diet (WD; 41% fat, 0.2% cholesterol) feeding to both wild-type (WT) and low density lipoprotein receptor knockout (Ldlr-/-) mice. A key finding was that hepatic cholesterol accumulation is a major driver of the progression of NAFLD to NASH. Accordingly, the most severe phenotype resulted from feeding the WD to Ldlr-/- mice. To evaluate the ability of C20-22 (n-3) PUFA to combat NAFLD/NASH, mice were fed the experimental diets with and without added C20-22 (n-3) PUFA over the entire feeding period (12 or 16 weeks). Addition of C20-22 (n-3) PUFA found in menhaden oil prevented the development of NAFLD in WT and Ldlr-/- mice fed either HF or HFHC diets for 12 weeks. However, when Ldlr-/- mice were fed the WD supplemented with C20-22 (n-3) PUFA for 16 weeks, hepatic steatosis developed but hepatic inflammation, oxidative stress, and fibrosis were dramatically attenuated. Furthermore, the capacity of dietary docosahexaenoic acid (DHA; C22:6 (n-3)) was greater than dietary eicosapentaenoic acid (EPA; C20:5 (n-3)) at attenuating WD induced hepatic inflammation, oxidative stress, and fibrosis in Ldlr-/- mice. To further investigate these findings, I used a metabolomics approach to assess the development of NASH and the impact from EPA and DHA supplementation. Development of NASH was wide-reaching and impacted all major pathways of hepatic metabolism analyzed including lipid, carbohydrate, and amino acid metabolism. There was very strong evidence of membrane lipid remodeling associated with NASH. These changes were most effectively prevented by supplementation with DHA. Additionally, C20-22 (n-3) PUFA supplementation dramatically elevated the accumulation of (n-3) derived oxidized PUFA with anti-inflammatory properties. Since DHA supplementation most potently attenuated NASH progression, I speculate that membrane remodeling and the corresponding changes in oxidized PUFA associated with DHA consumption plays a major role in attenuating inflammation, fibrosis, and oxidative stress in WD-induced NASH in Ldlr-/- mice. In conclusion, I established that the development of NASH has wide-reaching and complex consequences on hepatic metabolism. Ultimately, dietary DHA is more efficacious than dietary EPA at attenuating the progression of NASH induced by a severe model such as WD feeding to Ldlr-/- mice. Collectively, my data indicates that dietary DHA at a physiologically relevant dose, either alone or in combination with other therapy is likely to provide significant benefit to obese humans with NAFLD/NASH
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