The role of lecithin:Cholesterol acyltransferase for the low density lipoprotein composition and specific binding to the b receptor

Zechner, Rudolf; Dieplinger, Hans; Roscher, Adelbert A.; Krempler, Franz; Kostner, Gerhard M.

doi:10.1016/0005-2760(82)90365-4

Cited by 18 publications

(3 citation statements)

References 9 publications

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“…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. Thus, it is unclear whether the higher rates of high-affinity LDL degradation and the increases in cholesterol biosynthesis by freshly isolated mononuclear cells from patients treated with colestipol, which were observed in the present study, are related to changes in LDL composition that result from an increased fractional catabolic rate of this lipoprotein.…”

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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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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“…The binding affinity to the B/E receptor can be influenced by artificial alterations of the LDL structure (Steinberg et al, 1978). In a preliminary report (Zechner et al, 1982) pathway. In addition, more detailed information is provided on changes in the lipid and apolipoprotein composition of LCAT-modified LDL.…”

Section: Discussionmentioning

confidence: 99%

The low-density-lipoprotein pathway of native and chemically modified low-density lipoproteins isolated from plasma incubated in vitro

Zechner¹,

Dieplinger²,

Roscher³

et al. 1984

Biochemical Journal

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Normal fasting human plasma was incubated for 24 h at 37 degrees C in the presence or absence of lecithin:cholesterol acyltransferase (LCAT) inhibitors. The low-density lipoprotein (LDL) fractions of incubated plasma (control LDL and LCAT-modified LDL) were studied with respect to their chemical and functional properties. LCAT-modified LDL differed from control LDL by a decreased phospholipid and free-cholesterol content, but increased cholesteryl esters. Furthermore, an increase of the relative protein content in LDL by 16-20% was found. Apolipoproteins of LCAT-modified LDL exhibited a 10-fold increase of apo AI, a 4-5-fold increase of apo E, and a 2-fold increase of apo C. All these apolipoproteins resided together with apo B on the same particles. LCAT-modified LDL displayed a higher electrophoretic mobility, a higher hydrated density, a decreased flotation constant and a smaller diameter. Cultured human fibroblasts bound and internalized LCAT-modified LDL to a lower extent than control LDL. The degradation, however, was faster. Modified LDL suppressed 3-hydroxy-3-methylglutaryl-CoA reductase activity to a lower extent than did control LDL. Our results demonstrate that LCAT action, together with lipid transfer and exchange processes, markedly alters the chemical and physiochemical properties of LDL. This in turn significantly influences LDL catabolism in vitro.

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“…The LDL analyses were performed in a Beckman Model E analytical ultracentrifuge equipped with Schlieren optics and using a four-hole rotor An-F. Runs were carried out at 48 000 rpm and 20 °C for 3 h. Photographs were taken every 16 min as described (Zechner et al, 1982). The lipoprotein fractions were analyzed at a concentration of 10-15 mg/mL in a NaBr density solution of 1.090 g/mL, pH 7.4.…”

Section: Methodsmentioning

confidence: 99%

Action of lecithin-cholesterol acyltransferase on low-density lipoproteins in native pig plasma

Knipping¹,

Birchbauer²,

Steyrer³

et al. 1987

Biochemistry

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The action of lecithin-cholesterol acyltransferase (LCAT, EC 2.3.1.43) on the different pig lipoprotein classes was investigated with emphasis on low-density lipoproteins (LDL). It was demonstrated previously that LDL can serve as substrate for LCAT, probably because they contain sufficient amounts of apoA-I and other non-apoB proteins, known as LCAT activators. Upon a 24-h incubation of pig plasma in vitro in the presence of active LCAT, both pig LDL subclasses, LDL-1 and LDL-2, fused together, forming one fraction, as revealed by analytical ultracentrifugation. This fusion was time dependent, becoming visible after 3 h and complete after 18 h of incubation. Concomitantly, free cholesterol and phospholipids decreased and cholesteryl esters increased. When isolated LDL-1 and LDL-2 were incubated with purified pig LCAT for 24 h, LDL-1 floated toward higher densities and LDL-2 toward lower densities, although this effect was not as pronounced as in incubations of whole serum. In further experiments, pig serum was incubated for various periods of time in the presence and absence of the LCAT inhibitor sodium iodoacetate. The individual lipoproteins then were separated by density gradient ultracentrifugation or by specific immunoprecipitation and chemically analyzed. Both methods revealed that in the absence of active LCAT there was a transfer of free cholesterol from LDL to high-density lipoproteins (HDL) and a small transfer of cholesteryl esters in the opposite direction. In the presence of LCAT the loss of free cholesterol started immediately in all three lipoprotein classes, was most prominent in LDL, and was proportional to the newly synthesized cholesteryl esters incorporated in each fraction.(ABSTRACT TRUNCATED AT 250 WORDS)

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The role of lecithin:Cholesterol acyltransferase for the low density lipoprotein composition and specific binding to the b receptor

Cited by 18 publications

References 9 publications

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

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

The low-density-lipoprotein pathway of native and chemically modified low-density lipoproteins isolated from plasma incubated in vitro

Action of lecithin-cholesterol acyltransferase on low-density lipoproteins in native pig plasma

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