Reversible abnormalities of low density lipoprotein composition in familial hypercholesterolaemia

Jadhav, Arvind; Thompson, Gilbert R.

doi:10.1111/j.1365-2362.1979.tb01668.x

Cited by 40 publications

(13 citation statements)

References 24 publications

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“…These findings contrast with those in patients with FH, in whom there is an increase in the more buoyant LDL particles, which are relatively cholesterol enriched and protein depleted. The present findings are also consistent with the previous reports of altered LDL in FH (20,(27)(28)(29).…”

Section: Discussionsupporting

confidence: 94%

“…A possible explanation for the decreased cholesterol-toprotein ratio in hyperapoB might be a shift in the spectrum of LDL towards smaller, denser particles. In contrast, LDL from patients with FH has a higher than normal cholesterol-to-protein ratio (20), suggestive of a shift towards larger, less dense particles. To test this hypothesis, we investigated the pattern of distribution of LDL in normal subjects, as well as patients with hyperapoB and FH, by means of density gradient ultracentrifugation.…”

mentioning

confidence: 89%

“…To examine the physical basis for the apparent disproportion between LDL cholesterol and apoB characteristic of this syndrome, we used density gradient ultracentrifugation to isolate LDL fractions from 10 normal subjects, from 20 patients with hyperapobetalipoproteinemia (10 normotriglyceridemic and 10 hypertriglyceridemic), and from 7 patients with familial hypercholesterolemia. In familial hypercholesterolemia, more LDL was in fraction 1-"light" LDL-and this LDL was relatively enriched in cholesterol-and poor in protein.…”

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confidence: 99%

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Composition and distribution of low density lipoprotein fractions in hyperapobetalipoproteinemia, normolipidemia, and familial hypercholesterolemia.

Teng¹,

Thompson²,

Sniderman³

et al. 1983

Proc. Natl. Acad. Sci. U.S.A.

195

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Hyperapobetalipoproteinemia is defined as the combination of a normal low density lipoprotein (LDL) cholesterol in the face of an increased LDL apolipoprotein B (apoB) protein.To examine the physical basis for the apparent disproportion between LDL cholesterol and apoB characteristic of this syndrome, we used density gradient ultracentrifugation to isolate LDL fractions from 10 normal subjects, from 20 patients with hyperapobetalipoproteinemia (10 normotriglyceridemic and 10 hypertriglyceridemic), and from 7 patients with familial hypercholesterolemia. In familial hypercholesterolemia, more LDL was in fraction 1-"light" LDL-and this LDL was relatively enriched in cholesterol-and poor in protein. By contrast, it was fraction 2 "heavy" LDL-that differed in hyperapobetalipoproteinemia, being denser, depleted of cholesterol (particularly cholesteryl ester), and relatively enriched in apoB. These findings were more pronounced in the hypertriglyceridemic patients than in the normotriglyceridemic patients with hyperapobetalipoproteinemia. Thus this study confirms that considerable heterogeneity exists between LDL subfractions within individuals but, in addition, indicates there are also marked-and apparently characteristicdifferences in LDL composition amongst normal subjects and patients with hyperapobetalipoproteinemia or familial hypercholesterolemia.The risk of coronary heart disease in the Framingham study was initially shown to be related to plasma total cholesterol (1) and subsequently to the levels of cholesterol in the major lipoprotein classes (2,3). Recently, several studies have suggested that quantitation of the apoprotein moieties of these lipoproteins can provide additional information in this respect (4-12). In particular, the plasma concentration of the major apoprotein of low density lipoprotein (LDL), apolipoprotein B (apoB), may frequently be increased in patients with coronary disease despite their having an LDL cholesterol within the normal range, a combination we termed hyperapobetalipoproteinemia (hyperapoB) (4, 10). By contrast, patients with familial hypercholesterolemia (FH), in whom the risk of coronary heart disease is also very high, exhibit increases in both LDL cholesterol and LDL apoB.LDL are spherical particles that range in diameter between 21.0 and 29.0 nm and in density between 1.019 and 1.063 g/ ml. Not surprisingly, there is mounting evidence that considerable heterogeneity exists among these LDL particles (13)(14)(15)(16)(17)(18). For example, Shen et al. (16), using density gradient ultracentrifugation, demonstrated marked diversity of LDL in terms of both size and composition in normal individuals, the larger particles being enriched in cholesteryl ester compared to the smaller protein-enriched particles. In addition, Fisher and his colleagues have shown in a series of studies that in some individuals LDL is monodisperse, whereas in others it is polydisperse (19). A possible explanation for the decreased cholesterol-toprotein ratio in hyperapoB might be a shift in the ...

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Section: Discussionsupporting

confidence: 94%

mentioning

confidence: 89%

mentioning

confidence: 99%

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Composition and distribution of low density lipoprotein fractions in hyperapobetalipoproteinemia, normolipidemia, and familial hypercholesterolemia.

Teng¹,

Thompson²,

Sniderman³

et al. 1983

Proc. Natl. Acad. Sci. U.S.A.

195

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“…The increase in SM was related to an increased ratio of free to esterified cholesterol in LDL. The changes were in part reversed after LDL apheresis, when newly produced LDLs predominate, indicating that they are linked to prolonged residence time in plasma for the LDL particles (120,142). The few data on type III human hyperlipidemia also reveal that the accumulation of remnant particles is linked to an increase in SM level in the lipoproteins (143).…”

Section: Causes Of Hypersphingomyelinemiamentioning

confidence: 88%

Absorption and lipoprotein transport of sphingomyelin

Nilsson

Duan

2006

Journal of Lipid Research

227

201

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Dietary sphingomyelin (SM) is hydrolyzed by intestinal alkaline sphingomyelinase and neutral ceramidase to sphingosine, which is absorbed and converted to palmitic acid and acylated into chylomicron triglycerides (TGs). SM digestion is slow and is affected by luminal factors such as bile salt, cholesterol, and other lipids. In the gut, SM and its metabolites may influence TG hydrolysis, cholesterol absorption, lipoprotein formation, and mucosal growth. SM accounts for z20% of the phospholipids in human plasma lipoproteins, of which two-thirds are in LDL and VLDL. It is secreted in chylomicrons and VLDL and transferred into HDL via the ABCA1 transporter. Plasma SM increases after periods of large lipid loads, during suckling, and in type II hypercholesterolemia, cholesterol-fed animals, and apolipoprotein E-deficient mice. SM is thus an important amphiphilic component when plasma lipoprotein pools expand in response to large lipid loads or metabolic abnormalities. It inhibits lipoprotein lipase and LCAT as well as the interaction of lipoproteins with receptors and counteracts LDL oxidation. The turnover of plasma SM is greater than can be accounted for by the turnover of LDL and HDL particles. Some SM must be degraded via receptor-mediated catabolism of chylomicron and VLDL remnants and by scavenger receptor class B type I receptor-mediated transfer into cells. Sphingomyelin (SM) in mammalian cells is colocalized with cholesterol mainly in the plasma membrane and in lysosomal and Golgi membranes. It interacts strongly with cholesterol, and the regulation of SM and cholesterol metabolism are in part coordinated (1, 2). In plasma lipoproteins, SM is the second most abundant polar lipid after phosphatidylcholine (PC). The size of the plasma lipoprotein SM pool in humans is 1-1.5 g, of which approximately two-thirds are in apolipoprotein B (apoB)-containing triglyceride (TG)-rich lipoproteins and LDL. The SM content in most extraneural tissues is 1-2 g/kg. Factors regulating plasma SM concentration have received little attention. It was early shown that the level of SM is increased in hypercholesterolemia and that SM-rich lipoproteins accumulate in arteriosclerotic lesions (3-5). Plasma SM is thus a risk factor for ischemic heart disease (6), and the apoE-deficient (apoE 2/2 ) mouse, which accumulates SM-rich remnant particles in blood (7), has emerged as an important model for studying the role of SM in atherogenesis. The effects of lipoprotein SM in the arterial wall during atherogenesis may be related both to the modification of lipoproteins and to the generation of sphingolipid messengers (i.e., ceramide, ceramide-1-phosphate, sphingosine, and sphingosine-1-phosphate) initiated by SM hydrolysis (8-10). The role of SM metabolites in cell signaling has been the subject of several recent reviews (11)(12)(13)(14)(15)(16). Sphingolipid signals are triggered by numerous stimuli and mediate effects on cell growth and apoptosis and on the activities of inflammatory cells that may be pathogenic as well as protect...

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“…These differences include an increase in the cholesterol/phospholipid ratio, an increase in the proportion of cholesterol esters, and an abnormally low lecithin/sphingomyelin ratio. These acquired changes, which are believed to reflect decreases in the fractional rate of catabolism of LDL, are more pronounced in patients with homozygous FH and can be partially ameliorated by plasma exchange therapy or by treatment with colestipol or cholestyramine (31). Although increases in the cholesterol ester and sphingomyelin content of LDL have been reported to decrease its binding affinity to the high-affinity LDL receptors on cultured human fibroblasts (34), an earlier study (35) showed no difference in the rates of cellular metabolism of LDL isolated from the plasma of normal subjects as compared with that from patients with homozygous FH.…”

Section: Discussionmentioning

confidence: 99%

Effects of hypolipidemic therapy on cholesterol homeostasis in freshly isolated mononuclear cells from patients with heterozygous familial hypercholesterolemia.

Sundberg¹,

Illingworth²

1983

Proc. Natl. Acad. Sci. U.S.A.

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Freshly isolated mononuclear leukocytes have been reported to-show changes in cholesterol synthesis and high-affinity degradation of low-density lipoproteins (LDL) that parallel those that occur in the liver. To examine whether hypolipidemic therapy in patients with heterozygous familial hypercholesterolemia influences cholesterol homeostasis in their mononuclear cells we assessed the effects of colestipol and nicotinic acid (alone and in combination) on the rates of high-affinity "SI-labeled LDL degradation and on the rates of cholesterol and phosphatidylcholine biosynthesis by freshly isolated cells. Rates of '25I-labeled LDL degradation were lower in mononuclear cells from patients with heterozygous familial hypercholesterolemia on no medication (3.1 ng per 4 X 106 cells per 5 hr) than in cells from normal control subjects (6.1 ng per 4 X 106 cells per 5 hr) and, in the former patients, the values were not significantly affected by therapy with nicotinic acid. In contrast, freshly isolated mononuclear cells from patients receiving colestipol degraded "2I-labeled LDL at nearnormal rates (5.0 ng per 4 x 106 cells per 5 hr). The rates of cholesterol synthesis were also higher in mononuclear cells isolated from patients treated with colestipol than in cells from untreated patients or from those receiving nicotinic acid; in contrast the rate of synthesis of phosphatidylcholine did not show any consistent changes. Similar results were obtained in a smaller number of patients studied longitudinally, in which colestipol therapy significantly increased rates of cholesterol synthesis and high-affinity degradation of '25I-labeled LDL by freshly isolated mononuclear cells. We conclude that previously observed changes in cholesterol homeostasis in the liver of patients treated with bile acid sequestrants are paralleled by similar changes in freshly isolated mononuclear cells and that these cells offer an accessible model for further studies on how diet and pharmacologic agents influence cellular cholesterol homeostasis in humans.Optimal treatment of patients with heterozygous familial hypercholesterolemia (FH) necessitates the use of diet and hypolipidemic medication, among which the bile acid-binding resins (colestipol and cholestyramine) and nicotinic acid are the most efficacious (1,2). Recent studies have clarified the mechanisms by which colestipol and cholestyramine decrease plasma concentrations of low-density lipoproteins (LDL) in both experimental animals and in humans (3, 4). Both drugs bind bile acids in the intestinal lumen, thereby interrupting the enterohepatic circulation and stimulating an increase in the hepatic conversion of cholesterol to bile acids. This in turn depletes the hepatic pool of cholesterol and results in two compensatory changes; an increase in the de novo biosynthesis of cholesterol (5) has been shown in humans and an increase in the number of specific high-affimity LDL receptors on hepatocyte membranes has been shown in rabbits and dogs (4, 6). The latter change also promotes an...

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Reversible abnormalities of low density lipoprotein composition in familial hypercholesterolaemia

Cited by 40 publications

References 24 publications

Composition and distribution of low density lipoprotein fractions in hyperapobetalipoproteinemia, normolipidemia, and familial hypercholesterolemia.

Composition and distribution of low density lipoprotein fractions in hyperapobetalipoproteinemia, normolipidemia, and familial hypercholesterolemia.

Absorption and lipoprotein transport of sphingomyelin

Effects of hypolipidemic therapy on cholesterol homeostasis in freshly isolated mononuclear cells from patients with heterozygous familial hypercholesterolemia.

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