Cholesterol synthesis and regulation: Cholesterol and the brain

Cholesterol synthesis and regulation

Cholesterol and the brain

Mammalian brain function is dependent on special-ized membranes designed for signal transmission. Greater cognitive sophistication in humans appears to depend on a much greater number of connections and, consequently, greater potential for signal pro-cessing. Like the membrane lipids of most other mammalian organs, brain lipids contain a relatively high proportion of cholesterol, which increases from about 40% of the lipid content in neonates to nearly 50% in adults.

Unlike other organs, the mammalian brain is prob-ably unique in being unable to acquire appreciable amounts of cholesterol from the circulation, i.e., from the diet or from synthesis outside the brain. This has been extensively studied in the young rat and sup-porting, although inconclusive, evidence is also avail-able for the pig. The brain has sufficient capacity to synthesize cholesterol from acetyl-CoA derived pri-marily from either glucose or ketones. Hence, it achieves the required level of cholesterol apparently entirely by endogenous synthesis. In neonates, ketones appear to play a greater role as substrates for brain cholesterol than in adults, in whom their main func-tion seems to be as an alternative fuel to glucose. Among the common dietary long-chain fatty acids that would give rise to ketones during fat oxidation, PUFAs, particularly linoleate and α-linolenate, appear to be the best substrates for ketogenesis, since carbon from these fatty acids readily appears in brain choles-terol in suckling rats.