Anti oxidative acyl CoA Cholesterol acyl transferase Inhibitor Avasimibe reduces the impact of high cholesterol diet on Brain lipid peroxidation in mice

Objectives: High fat/high cholesterol diet (HFD) is a risk factor for Alzheimer's Disease (AD). Cholesterol lowering drugs are potential therapies for AD and assessment of the cholesterol-lowering drug Avasimibe was used to assess potential therapeutic effects on liver cholesterol metabolism and its role in the improvement in brain lipid peroxidation and neurodegeneration.
Methods: The anti-oxidative acylCoA cholesterol acyltransferase (ACAT) inhibitor Avasimibe was administered orally (diet) to mice. Diet-induced hypercholesterolemia was used as a model in mice to assess the relationship between steatosis (hepatic dysfunction) and oxidative damage associated with neurodegeneration (brain). Lipid identification and characterization of the brain was conducted with lipidomics.
Results: In mice fed the HFD there was an increase in brain free cholesterol content and an increase in brain cholesterol oxidation (as assessed by 24S-hydroxycholesterol levels). The HFD diet altered phosphatidylinositol turnover in mouse brain membranes. Avasimibe could be detected in the plasma but not in the brain and was found to inhibit ACAT activity in the periphery only yet was associated with therapeutic improvements in brain lipid composition as shown in the image.
Conclusions: The HFD diet induced steatosis (fatty liver) and treatment with Avasimibe reduced liver and brain lipid accumulation and improved brain lipid composition. Avasimibe improved diet-induced brain oxidative stress with reduction of brain cholesterol oxidation and phospholipid peroxidation (vitamin E sensitive) thus preventing neurodegeneration.