Body Cholesterol Metabolism in Man. I. The Equilibration of Serum and Tissue Cholesterol*†

Chobanian, Aram V.; Hollander, William

doi:10.1172/jci104631

Cited by 184 publications

(74 citation statements)

References 7 publications

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“…This has been demonstrated previously in man (22). Nevertheless, the specific radioactivity of free cholesterol was always slightly higher in the liver than in plasma (Table II); this finding has also been reported in the rat (2).…”

Section: Discussionsupporting

confidence: 88%

Turnover of individual cholesterol esters in human liver and plasma.

Nestel¹,

Couzens²

1966

J. Clin. Invest.

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There are several lines of evidence which suggest that the liver is a major source of plasma cholesterol esters. First, eviscerated rats cannot maintain a normal concentration of cholesterol esters in the plasma (1); second, when isotopically labeled mevalonic acid is administered to rats, the specific radioactivity of the hepatic cholesterol esters initially exceeds that of the plasma cholesterol esters (2); and third, the perfusion of livers from cholesterol-fed rats leads to an increased secretion of cholesterol esters from the liver into the perfusate (3).Despite this, the composition of cholesterol esters in the liver and plasma is dissimilar, both in the rat (2, 3) and in man (4,5). This has raised the question of whether an additional source of plasma cholesterol esters exists outside the liver. A transesterification reaction between free cholesterol and the beta fatty acid of lecithin has been demonstrated in plasma and could account for a portion of the plasma cholesterol esters (6, 7). Simultaneous esterification of cholesterol in liver and plasma could lead to the formation of cholesterol esters of differing composition.Some of the factors that govern the formation and composition of cholesterol esters have been determined in the rat. The turnover of cholesterol esters in rat liver and plasma is heterogeneous. The fractional turnover rate of plasma cholesteryl oleate is greater than that of the other esters (2) and may be related to the high degree of specificity for cholesteryl oleate formation by liver enzymes (8). When rats are fed cholesterol with different fatty acids, cholesteryl oleate accumulates in the * Submitted for publication November 1, 1965; accepted April 18, 1966. Supported by a grant from the National Heart Foundation of Australia. liver irrespective of the fatty acid fed, yet cholesteryl arachidonate remains the predominant ester in the plasma and is the major cholesterol ester secreted by the liver in the fasting rat (9).The heterogeneity of plasma cholesterol ester turnover found in the rat does not apply in man. Goodman (10) has demonstrated a similarity in the fractional turnover rates of individual cholesterol esters within a given class of plasma lipoproteins. This finding has been confirmed by Nestel, Couzens, and Hirsch (5), who have shown this to apply equally in men with low and high plasma cholesterol concentrations.This paper reports further studies in man in which the incorporation of radioactivity into the individual cholesterol esters of liver and plasma has been measured. We have compared the specific radioactivities of individual esters in liver and plasma in order to determine, first, whether the turnover of cholesterol esters is homogeneous in the liver as it is in the plasma, and second, whether the plasma esters can be shown to be derived from those in the liver. MethodsThe incorporation of either cholesterol-4-'4C 1 or dlmevalonic acid-2-'H 1 into the cholesterol esters of liver and plasma was studied in five subjects in whom abdominal surgery was carried out...

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Section: Discussionsupporting

confidence: 88%

Turnover of individual cholesterol esters in human liver and plasma.

Nestel¹,

Couzens²

1966

J. Clin. Invest.

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“…12 At approximately the Studies by Chobanian et al in the 1960s clearly demonstrated that the situation is similar in humans. 15 After intravenous injection of a bolus dose of 14 C-labeled cholesterol to terminally ill patients, they observed that the brain contained essentially no label, even after postinjection intervals of up to 7 months. Furthermore, as judged from the extent of incorporation of deuterium in cerebrospinal fluid (CSF) cholesterol after the intravenous infusion of deuterium-labeled cholesterol in a healthy volunteer, CSF cholesterol was found to be predominantly derived from the brain.…”

Section: Isolation Of Brain Cholesterolmentioning

confidence: 99%

Brain Cholesterol: Long Secret Life Behind a Barrier

Björkhem

Meaney

2004

ATVB

894

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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“…53 Many years ago several groups, including Chobanian and Hollander 54 and Jagannathan et al 55 , measured the specific activity of cholesterol in plaques excised from patients who were given radioactive cholesterol to measure cholesterol pool sizes. The cholesterol-specific activity was low when compared to plasma, and these researchers concluded that the turnover rate of cholesterol in atheroma is slow.…”

Section: Equilibration Of Cholesterol Between Plasma and Plaque Phasesmentioning

confidence: 99%

George Lyman Duff memorial lecture. Progression and regression of atherosclerotic lesions. Insights from lipid physical biochemistry.

1988

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This review summarizes the evidence that the physical properties of lipids which accumulate in the intima play major roles in the progression and regression of lesions of atherosclerosis. All of the three major classes of lipids that accumulate in lesions (phospholipids, cholesterol, and cholesterol esters) are water insoluble. Phospholipids and cholesterol esters are almost mutually insoluble, but cholesterol, a crystalline solid at 37 degrees C, has considerable solubility in phospholipid bilayers and cholesterol esters. In normal infant intima, cholesterol is solubilized by phospholipid membranes. During fatty streak development, groups of cells are stimulated to take up more cholesterol than they excrete. The excess cholesterol is biochemically converted to cholesterol ester, which separates as droplets to form foam cells. Some fatty streaks then undergo a transition to an intermediate lesion containing excess cholesterol which is carried in cholesterol-supersaturated membranes and droplets. When nucleation of this excess cholesterol occurs, it precipitates as crystals; their formation coincides with the onset of necrosis and plaque formation. The hallmark of plaque is the presence of inert cholesterol crystals. They appear to form from hydrolysis of the older deposits of cholesterol esters in the base of intermediate lesions. Thus, the lipids in plaques are stratified, with recently deposited cholesterol esters present in the luminal part of the intima and older deposits in the deeper regions. When plasma cholesterol is lowered below about 150 mg/dl, lipids are mobilized from lesions and regression gradually occurs. Early in the regression process, cholesterol esters are reduced at least partly by hydrolysis to yield cholesterol, some of which may crystallize and inhibit rapid regression. After prolonged periods of low plasma cholesterol, cholesterol esters and foam cells disappear and crystalline cholesterol gradually dissolves, leading to true regression.

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Body Cholesterol Metabolism in Man. I. The Equilibration of Serum and Tissue Cholesterol*†

Cited by 184 publications

References 7 publications

Turnover of individual cholesterol esters in human liver and plasma.

Turnover of individual cholesterol esters in human liver and plasma.

Brain Cholesterol: Long Secret Life Behind a Barrier

George Lyman Duff memorial lecture. Progression and regression of atherosclerotic lesions. Insights from lipid physical biochemistry.

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