(LB03-06-24) Effects of Fish Oil on Liver Tissue in an Amyloidogenic Alzheimer’s Mouse Model

Objectives: Alzheimer's Disease (AD) is a neurodegenerative disease caused by atypical aggregation of amyloid beta (Aß) and tau proteins in the brain. Obesity and associated metabolic dysfunctions are heavily implicated as risk factors for AD. As a central regulator in metabolism, liver inflammation increased by high-fat (HF) diet, may subsequently affect the AD pathogenesis in the body. Our lab previously reported the protective effect of eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acid from fish oil, in reducing circulating Aß levels in a mouse model, however, the mechanism remains unknown. Hence, we hypothesized that the above anti-amyloidogenic effect of EPA is partially mediated through the improvement of lipid metabolism in the liver, including lipogenesis reduction and lipolysis enhancement.

Methods: Two-month-old male and female APPswePS1E9 transgenic (TG) and non-TG littermates (WT) were randomized to low-fat (LF), or HF supplemented with or without 36g EPA/kg diet (HF-EPA) for 8 months. Weekly body weight and body composition were recorded. At study termination, liver tissues were collected for histological examination, and gene and protein analysis. RNA expression and protein expression were analyzed by two-way ANOVA and three-way ANOVA respectively using GraphPad Prism 10.

Results: WT female mice treated with EPA exhibited reduced expression of acetyl-CoA carboxylase alpha (ACACA), a gene involved in fatty acid synthesis, compared to the HF group (p < 0.05). In addition, in TG females, compared to HF, mice treated with EPA expressed significantly increased expression of proteins involved in autophagy, like LC3 (P < 0.01), and cell cycle, like total-AKT, (P < 0.01). Lastly, H&E staining of liver sections was used to visually assess lipid accumulation, and we observed that TG males and WT females in HF-EPA groups appeared to have fewer and smaller lipid droplets than those in HF groups

Conclusions: Fish oil supplementation reduced hepatic fat accumulation and genes related to fatty acid synthesis. Additionally, in TG females, HF-EPA increased markers for autophagy and cellular proliferation compared to HF. Our findings warrant further studies on the effects of fish oil in reducing the effects of a high-fat diet and the risk of AD.

Funding Sources: NIH (NCCIH and NIA) grant #R15AT008879-01A1