The cholesteryl ester transfer protein (CETP) raises cholesterol levels in the brain

The cholesteryl ester transfer protein (CETP) is a lipid transfer protein responsible for the exchange of cholesteryl esters and triglycerides between lipoproteins. Decreased CETP activity is associated with longevity, cardiovascular health, and maintenance of good cognitive performance. Interestingly, mice lack the CETP-encoding gene and have very low levels of LDL particles compared with humans. Currently, the molecular mechanisms induced because of CETP activity are not clear. To understand how CETP activity affects the brain, we utilized CETP transgenic (CETPtg) mice that show elevated LDL levels upon induction of CETP expression through a high-cholesterol diet. CETPtg mice on a high-cholesterol diet showed up to 22% higher cholesterol levels in the brain. Using a microarray on mostly astrocyte-derived mRNA, we found that this cholesterol increase is likely not because of elevated de novo synthesis of cholesterol. However, cholesterol efflux is decreased in CETPtg mice along with an upregulation of the complement factor C1Q, which plays a role in neuronal cholesterol clearance. Our data suggest that CETP activity affects brain health through modulating cholesterol distribution and clearance. Therefore, we propose that CETPtg mice constitute a valuable research tool to investigate the impact of cholesterol metabolism on brain function.