Ontogenesis and regulation of cholesterol metabolism in the central nervous system of the mouse.

ABSTRACT

These studies characterized the ontogenesis and regulation of cholesterol turnover in the central nervous system (CNS) of mice. During the first 3 weeks after birth, the CNS grew rapidly and equaled 5% of body weight. The cholesterol pool in this tissue expanded at a rate of 0.26 mg/day and the CNS synthesized sterol at a rate of 0.28 mg/day. In mature mice between 13 and 26 weeks of age, there was a marked decrease in these parameters including a reduction in the relative size of the CNS to 1.7% of body weight, a decrease in the rate of sterol accretion to 0.012 mg/day, and a reduction in the rate of cholesterol synthesis to 0.035 mg/day. Deletion of the NPC1 and CYP46A1 proteins markedly altered cholesterol metabolism in the CNS. However, changes in the plasma cholesterol concentration or loss of function of ATP-binding cassette AI transporter (ABCA1), scavenger receptor class B, type I (SR-BI), low-density lipoprotein receptor (LDLR), APOE or APOAI had no effect on sterol turnover in the brain. Thus, during early development, cholesterol comes entirely from local synthesis. In the adult, however, synthesis exceeds the need for structural cholesterol so that there is a constant excretion of sterol from the CNS into the plasma at a rate of about 0.023 mg/day.