The effect of a western diet on the synthesis and metabolism of cholesterol in the brain

Purpose: Cholesterol is an important molecule in the brain however the effect of diet on cholesterol synthesis and metabolism in the brain has not been characterised. The purpose of this study was to identify levels of cholesterol synthetic precursors, metabolic and oxidation products as well as phytosterols in different brain regions. The effect of a westernised diet on brain levels of these compounds was also investigated. Method: A diet study was performed in male C57BL/6 mice, feeding diets high in fat (18% from ghee, 1% cholesterol) and heme (2.5%) over 4, 9 and 20 weeks (n=6 for each diet). Lipids were extracted from collected brain tissue and analysed for 16 compounds using a novel triple quadrupole gas chromatography-mass spectrometry method. Results: Significant differences between cortex and cerebellum were detected in 27-hydroxycholesterol and 24-hydroxycholesterol (P\u3c0.001); lathosterol and 24,25 dihydro lanosterol (P\u3c0.005), and desmosterol, zymosterol and 14-desmethyl cholesterol (P\u3c0.05). Dietary effects were detected with significant increases in the cholesterol oxidation products 7β-hydroxycholesterol (5 fold) and 7-ketocholesterol (2 fold) after 20 weeks of high fat-heme diet. A significant increase of 27-hydroxycholesterol was also measured in the cerebellum when mice were fed diets containing heme. The phytosterol campesterol accumulated in control brains while high fat containing diets did not show an increase. Conclusions: Different mouse brain regions have a specific profile of cholesterol synthetic precursors and metabolites. A westernised diet increases cholesterol oxidation products in the brain as well as the oxysterol 27-hydroxycholesterol. This may indicate increased oxidative stress and/or disruption of the blood brain barrier