Studies on the synthesis of cholesterol in the brain of the human fetus

Plotz, E. J.; Kabara, Jon J.; Davis, M. Edward; Leroy, Georges; Gould, R. Gordon

doi:10.1016/0002-9378(68)90565-6

Cited by 54 publications

(24 citation statements)

References 9 publications

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“…16 Finally, this isolation of the brain appears to be present from an early age; after administration of 14 C-cholesterol to pregnant women, there was essentially no label in fetal brain tissue, whereas significant amounts were present in liver and other viscera. 17 The blood-brain barrier prevents diffusion of large molecules at the level of tight junctional attachments between adjacent capillary endothelial cells. 18 Surprisingly, it has been shown that brain endothelial cells have the potential to take-up low-density lipoprotein (LDL) cholesterol through luminal LDL receptors and translocate this LDL across the cell.…”

Section: Isolation Of Brain Cholesterolmentioning

confidence: 99%

Brain Cholesterol: Long Secret Life Behind a Barrier

Björkhem

Meaney

2004

ATVB

892

732

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Abstract-Although an immense knowledge has accumulated concerning regulation of cholesterol homeostasis in the body, this does not include the brain, where details are just emerging. Approximately 25% of the total amount of the cholesterol present in humans is localized to this organ, most of it present in myelin. Almost all brain cholesterol is a product of local synthesis, with the blood-brain barrier efficiently protecting it from exchange with lipoprotein cholesterol in the circulation. Thus, there is a highly efficient apolipoprotein-dependent recycling of cholesterol in the brain, with minimal losses to the circulation. Under steady-state conditions, most of the de novo synthesis of cholesterol in the brain appears to be balanced by excretion of the cytochrome P-450 -generated oxysterol 24S-hydroxycholesterol. This oxysterol is capable of escaping the recycling mechanism and traversing the blood-brain barrier. Cholesterol levels and cholesterol turnover are affected in neurodegenerating disorders, and the capacity for cholesterol transport and recycling in the brain seems to be of importance for the development of such diseases. The possibility has been discussed that administration of inhibitors of cholesterol synthesis may reduce the prevalence of Alzheimer disease. No firm conclusions can, however, be drawn from the studies presented thus far.In the present review, the most recent advances in our understanding of cholesterol turnover in the brain is discussed. Key Words: brain cholesterol Ⅲ blood-brain barrier Ⅲ cholesterol 24S-hydroxylase Ⅲ Alzheimer disease Ⅲ statins H ighly sophisticated regulatory systems have evolved for the maintenance of cholesterol homeostasis in the body. There is a distinct difference between the situation in the central nervous system and that in most other extrahepatic tissues. Outside the brain, the cellular needs for cholesterol is covered by de novo synthesis and by cellular uptake of lipoprotein cholesterol from the circulation. In the brain, the blood-brain barrier effectively prevents uptake from the circulation, and de novo synthesis is responsible for practically all cholesterol present in this organ. The independence of the isolated pool of cholesterol in the brain is likely to reflect a high need for constancy in the cholesterol content of membrane and myelin, a constancy that would be difficult to keep if brain cholesterol had been exchangeable with lipoprotein cholesterol.The importance of cholesterol in the nervous system was recognized as early as 1834, when Couerbe's observations lead him to regard cholesterol as un element principal of the nervous system. 1 Despite concerted efforts in the interim, it is only during the past few decades that the brain has begun to surrender the secrets of the behavior of one of its most abundant lipids.In the present brief review, we summarize the basal characteristics of brain cholesterol and some recent findings with respect to homeostasis of this compound in the brain. Emphasis is put on the newly described relation betwee...

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Section: Isolation Of Brain Cholesterolmentioning

confidence: 99%

Brain Cholesterol: Long Secret Life Behind a Barrier

Björkhem

Meaney

2004

ATVB

892

732

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“…Importantly, the severity of the SLOS phenotype is affected by the apoE isoform expressed in the mothers but not the fathers (23). Second, though the reported rates of transport vary, some of the early human studies did indeed demonstrate a transfer of maternal cholesterol to the fetal circulation (24)(25)(26). Third, more recent studies in the mouse determined that ?20% of murine fetal cholesterol is derived from the maternal circulation (27,28).…”

mentioning

confidence: 99%

Transport of maternal cholesterol to the fetus is affected by maternal plasma cholesterol concentrations in the Golden Syrian hamster

Burke

Colvin

Myatt

et al. 2009

Journal of Lipid Research

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The fetus has a high requirement for cholesterol and synthesizes cholesterol at elevated rates. Recent studies suggest that fetal cholesterol also can be obtained from exogenous sources. The purpose of the current study was to examine the transport of maternal cholesterol to the fetus and determine the mechanism responsible for any cholesterol-driven changes in transport. Studies were completed in pregnant hamsters with normal and elevated plasma cholesterol concentrations. Cholesterol feeding resulted in a 3.1-fold increase in the amount of LDL-cholesterol taken up by the fetus and a 2.4-fold increase in the amount of HDL-cholesterol taken up. LDL-cholesterol was transported to the fetus primarily by the placenta, and HDL-cholesterol was transported by the yolk sac and placenta. Several proteins associated with sterol transport and efflux, including those induced by activated liver X receptor, were expressed in hamster and human placentas: NPC1, NPC1L1, ABCA2, SCP-x, and ABCG1, but not ABCG8. NPC1L1 was the only protein increased in hypercholesterolemic placentas. Thus, increasing maternal lipoprotein-cholesterol concentrations can enhance transport of maternal cholesterol to the fetus, leading to 1) increased movement of cholesterol down a concentration gradient in the placenta, 2) increased lipoprotein secretion from the yolk sac (shown previously), and possi- Cholesterol is essential for normal fetal development. Possibly the most noted role of cholesterol is as a structural component of membranes. Sterols are also the precursor for bile acids, steroid hormones, and oxysterols, which are all synthesized by the fetus and regulate various cellular processes. Cholesterol is also required for activation of sonic hedgehog (Shh), a protein involved in brain development, and for propagation of the Shh signal (1, 2). Cholesterol is obtained endogenously by de novo synthesis and exogenously by transfer of maternal cholesterol to the fetus. Interestingly, maternal plasma triglyceride and cholesterol concentrations increase during pregnancy in humans (3, 4), possibly an adaptation to maternal and fetal needs. However, whether these changes in maternal lipoprotein concentrations result in increased transport of maternal cholesterol to the fetus is unclear.Since the fetus does not come in direct contact with the maternal circulation, maternal cholesterol destined for the fetus must initially be taken up by the placenta and yolk sac prior to transport and delivery to the fetus. Indeed, the placenta and yolk sac take up maternal LDL-and HDLcholesterol at relatively elevated rates compared with other peripheral tissues (5). LDL is taken up by the LDL receptor (LDLR), which is expressed abundantly in the placenta but expressed at low levels, if at all, in the yolk sac (5, 6). LDL-derived sterol is transported to the lysosome/endosome pathway where the ester bond is hydrolyzed (7). The unesterified cholesterol is then transported by NiemannThese studies were supported by grants HD34089 (LAW) and GM31651 (FS) from the...

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“…In the third trimester of gestation, maternally-derived cholesterol reportedly contributes ϳ22-40% to the fetal cholesterol pool (14,24). However, this remains controversial (25). The molecular mechanisms accounting for the uptake of maternal cholesterol into the placenta, mainly as lipoprotein-associated cholesterol (42), and for subsequent transfer, if any, into the fetal circulation, are as yet poorly understood.…”

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confidence: 99%

Intrauterine growth restriction is associated with alterations in placental lipoprotein receptors and maternal lipoprotein composition

Wadsack

Tabano²,

Maier³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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Cellular cholesterol uptake is mainly mediated by the LDL receptor (LDL-R) and the scavenger receptor family. We hypothesized that expression levels of key receptors of these families were regulated differently in placentas from IUGR pregnancies with varying degrees of severity. Third-trimester placentas from IUGR pregnancies with (IUGR-S) and without (IUGR-M) fetal hemodynamic changes and from control (AGA) pregnancies were studied. LDL-R, LDL-Rrelated protein (LRP-1), and scavenger receptor class B type I (SR-BI) mRNA and protein levels were measured. Cholesterol concentration and composition of lipoproteins were analyzed enzymatically and by lipid electrophoresis, respectively, in maternal and umbilical cord blood. LDL-R mRNA levels in IUGR-M were similar to AGA but lower (P Ͻ 0.05) in IUGR-S. In contrast, LDL-R protein was twofold (IUGR-M) and 1.8-fold (IUGR-S) higher (P Ͻ 0.05) than in the AGA group. LRP-1 mRNA and protein levels were not altered in the IUGR cases. SR-BI mRNA was unchanged in IUGR, but protein levels were lower (P Ͻ 0.05) in IUGR-S than in the other groups. Maternal plasma concentrations of LDL cholesterol were higher (P Ͻ 0.05) in the AGA group (188.5 Ϯ 23.6 mg/dl) than in the IUGR-S group (154.2 Ϯ 26.1). Electrophoretic mobility of the LDL fraction in maternal plasma demonstrated significant changes in migration toward higher values (AGA 0.95 Ϯ 0.06, IUGR-M 1.12 Ϯ 0.11, P Ͻ 0.001; IUGR-S 1.28 Ϯ 0.20, P ϭ 0.002). We conclude that LDL-R and SR-BI levels are altered in IUGR pregnancies. These differences were associated with changes in LDL, but not HDL, mobility and cholesterol concentration in maternal circulation. pregnancy; placenta; lipids; fetal growth CHOLESTEROL HAS MULTIPLE BIOLOGICAL ROLES that include its functioning as a structural membrane component, precursor for steroid synthesis, and activator of various cellular processes (42). Extensive steroid hormone synthesis in the placenta and the rapid growth and development of the fetus make pregnancy a condition of high cholesterol demand in the feto-placental unit (23). In humans, both placental tissue (39) and fetal organs (5) have the capacity for de novo cholesterol synthesis. However, the high cholesterol demand in the fetal tissues may not be fully satisfied by endogenous means. A significantly higher cholesterol concentration in the umbilical vein compared with the arteries (33) suggests transfer from maternal or placental sources to the fetus. In the third trimester of gestation, maternally-derived cholesterol reportedly contributes ϳ22-40% to the fetal cholesterol pool (14, 24). However, this remains controversial (25). The molecular mechanisms accounting for the uptake of maternal cholesterol into the placenta, mainly as lipoprotein-associated cholesterol (42), and for subsequent transfer, if any, into the fetal circulation, are as yet poorly understood.Cellular uptake of maternal low-density lipoprotein (LDL), high-density lipoprotein (HDL), and very low-density lipoprotein (VLDL) is mainly mediated by two receptor familie...

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Studies on the synthesis of cholesterol in the brain of the human fetus

Cited by 54 publications

References 9 publications

Brain Cholesterol: Long Secret Life Behind a Barrier

Brain Cholesterol: Long Secret Life Behind a Barrier

Transport of maternal cholesterol to the fetus is affected by maternal plasma cholesterol concentrations in the Golden Syrian hamster

Intrauterine growth restriction is associated with alterations in placental lipoprotein receptors and maternal lipoprotein composition

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