Brain cholesterol synthesis

Our NMR studies confirmed earlier radiotracer reports (Sinclair, 1975 Dhopeswarkar Subramanian, 1975) that a-linolenate could be readily used by suckling rats for brain cholesterol synthesis, but they did not establish the quantitative extent to which this occurred for a-linolenate itself. We selected GC-IRMS for this purpose primarily because a quantitative comparison could be made for incorporation of V derived from a-linolenate into docosahexaenoate and individual lipids synthesized de novo. 

The lipid compositions of plasma membranes, endoplasmic reticulum and Golgi membranes are distinct 26 Cholesterol transport and regulation in the central nervous system is distinct from that of peripheral tissues 26 In adult brain most cholesterol synthesis occurs in astrocytes 26 The astrocytic cholesterol supply to neurons is important for neuronal development and remodeling 27 The structure and roles of membrane microdomains (rafts) in cell membranes are under intensive study but many aspects are still unresolved 28... 

In adult brain most cholesterol synthesis occurs in astrocytes. Apoprotein E (apoE) is the major apolipopro-tein of the CNS and it is secreted by astrocytes. In astrocyte cultures apoE appears in the media as cholesterol-rich particles of a size similar to peripheral HDL (5-12 nm) (Fig. 2-7). The ATP-dependent transporter ABCA1, expressed by both astrocytes and neurons, promotes the formation of the apoE-stabilized high-density lipoprotein (HDL)-sized particles from astrocytic cholesterol. 

The brain is one of the most cholesterol rich organs of the body and contains 25% of total body cholesterol [92]. While the body manages cholesterol metabolism primarily through the liver, the brain cholesterol compartment is essentially isolated from body cholesterol pools by the blood brain barrier (BBB). During early CNS development, the rate of cholesterol synthesis is quite high due to extensive myelination. As the brain matures, cholesterol synthesis and turnover slow dramatically with an estimated total turnover rate ranging from 4-6 months [93] in adult rat brain. The turnover rate is even slower in humans than in rodents (0.03% per day vs. 0.4% in rodent) [94]. 

Because the rate of cholesterol synthesis exceeds the actual rate of consumption, the brain has evolved a unique mechanism to export excess... 

Likhodii SS, Cunnane SC. Utilization of carbon from C-polyunsaluralcs in the synthesis of brain cholesterol in the neonatal rat a C-NMR study. Magn Reson Med 1995 34 803. 

Cholesterol synthesis is essential for normal development and maintenance of tissues that cannot obtain cholesterol from plasma lipoproteins, such as brain [3]. Furthermore, the biosynthetic pathway supplies non-steroidal isoprenoids that are required by all cells. Thus, it is not surprising that metabolic defects in the cholesterol biosynthetic pathway have devastating physiological consequences [8,9]. 

Severely reduced cholesterol synthesis is predicted to have severe consequences for development of the fetus because cholesterol is obtained only from the maternal circulation during the first trimester [11]. In addition, the brain is predicted to be severely affected because plasma lipoproteins cannot cross the blood-brain barrier and most, if not all, cholesterol needed for brain growth and function is synthesized locally (S.D. Turley, 1998) [3,13]. Indeed, severely affected SLOS infants who died soon after birth were found to have functionally null 7-DHC A7-reductase alleles [13], whereas less severely affected individuals likely have some residual 7-DHC A7-reductase catalytic activity. Simvastatin has been found to increase serum and cerebral spinal fluid cholesterol levels in SLOS patients that have partial 7-DHC A7-reductase activity, possibly due to transcriptional upregulation of the allele with residual activity (RE. Jira, 2000). 

In addition to the liver and intestine (where cholesterol upon incorporation as lipoproteins reaches blood circulation), cholesterol biosynthesis occurs in almost all tissues. The rates of cholesterol synthesis may be high in organs or tissues, such as liver, developing brain, skin (epidermis), adrenal glands, and malignant tumors, or it may be low as in mature brain, kidney. 

The inhibitory effect of orotic acid (and of bovine milk containing orotate) on cholesterol synthesis was observed [349,350]. Orally administered orotic acid decreases the cholesterol level in whole serum and in serum P-lipoproteins, but increases its level in the liver of treated rats [351]. However, orotic acid did not affect the amount of glycolipids and cholesterol in the brain of lysine-deficient rats [352]. 

Lanosterol is an important intermediate in cholesterol synthesis, and 14a-demethylation is established as a step in the pathway. Yoshida s laboratory had studied the yeast enzyme for many years and then demonstrated the reaction in rat liver microsomes in 1994 [2734]. Subsequently the reaction was also demonstrated in rat brain microsomes [2735]. 

In the early 1930 s, when the prime research aim was the commercial synthesis of the sex hormones (whose structures had just been elucidated), the principal raw material available was cholesterol extracted from the spinal cord or brain of cattle or from sheep wool grease. This sterol (as its 3-acetate 5,6-dibromide) was subjected to a rather drastic chromic acid oxidation, which produced a variety of acidic, ketonic and hydroxylated products derived mainly by attack on the alkyl side-chain. The principal ketonic material, 3j -hydroxyandrost-5-en-17-one, was obtained in yields of only about 7% another useful ketone, 3 -hydroxypregn-5-en-20-one (pregnenolone) was obtained in much lower yield. The chief acidic product was 3j -hydroxy-androst-5-ene-17j -carboxylic acid. All three of these materials were then further converted by various chemical transformations into steroid hormones and synthetic analogs ... 

CYP7A1 catalyzes the 7a-hydroxylation of cholesterol, the first and rate limiting step of bile acid synthesis. This is also the principal way to eliminate cholesterol. CYP7B1 is primarily expressed in brain and catalyzes the synthesis of various neurosteroids and also the 7a-hydroxylation of oxysterols. 

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