Reduction in cholesterol and low density lipoprotein synthesis after portacaval shunt surgery in a patient with homozygous familial hypercholesterolemia.

Bilheimer, David W.; Goldstein, Joseph L.; Grundy, Scott M.; Brown, Michael S.

doi:10.1172/jci108223

Cited by 237 publications

(111 citation statements)

References 30 publications

(30 reference statements)

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“…No persistent reduction in the HDL cho-lesterol values, which were low before drug treatment, resulted from probucol therapy in that report. 28 Apart from isolated case reports, 26 ' M the only large series describing normal HDL cholesterol values in homozygous FH patients is that by Kachadurian and Uthman. 31 The mean ( ± SD) HDL cholesterol value in that study of 52 such individuals was 53 ± 36 mg/dl with a range of 17 to 140 mg/dl.…”

Section: Discussionmentioning

confidence: 99%

Abnormalities of high density lipoproteins in homozygous familial hypercholesterolemia.

Goldberg¹,

Fless²,

Baker³

et al. 1984

Arteriosclerosis

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The possibility that low high density lipoprotein (HDL) levels may add to the risk of occlusive atherosclerosis in familial hyperchoiesteroiemia (FH) is supported by the frequency and severity of this finding in these patients, particularly homozygotes. To investigate this abnormality in greater detail, we measured HDL lipid and apoprotein values in nine homozygotes with FH. Compared to their unaffected relatives, they had markedly reduced HDL cholesterol and apo A-l and A-ll levels. The values found in heterozygote relatives were between those of homozygotes and those of controls. Density gradient ultracentrifugation of serum or isolated HDL from homozygotes demonstrated little or no HDL 2 ; there was also a shift of homozygotes' HDL to an above normal peak density (d = 1.15 g/ml). Heterozygotes had milder abnormalities. The reduced HDL in FH seems to be related to elevated low density lipoprotein levels although the pathophysiology is unknown. These findings add weight to the concept that HDL abnormalities contribute to the relentless course of atherosclerosis in familial hyperchoiesteroiemia. (Arteriosclerosis 4:472-478, September/October 1984)T he homozygous form of familial hyperchoiesteroiemia (FH) is characterized by extreme hyperchoiesteroiemia, the development of cutaneous xanthomata in childhood, and the occurrence of occlusive atherosclerotic vascular disease that is commonly fatal before age 20. 1 The disease is due to mutations of the gene that controls the cellular receptor for low density lipoprotein (LDL), which results in defective binding or internalization of this lipoprotein. Poorly regulated, receptor-independent pathways then form the predominant route for the uptake of LDL, which results in an excessive accumulation of cholesterol in the tissues. 2 The exact mechanism for the development of atherosclerosis in these patients is not well under-

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Section: Discussionmentioning

confidence: 99%

Abnormalities of high density lipoproteins in homozygous familial hypercholesterolemia.

Goldberg¹,

Fless²,

Baker³

et al. 1984

Arteriosclerosis

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“…In these patients, LDL degradation through the physiologic pathway is blocked, and each LDL particle survives in the circulation 2-3 times longer than it does in normal subjects (3)(4)(5). As a result, the lipoprotein accumulates to abnormally high levels in plasma.…”

Section: Abstracimentioning

confidence: 99%

Binding site on macrophages that mediates uptake and degradation of acetylated low density lipoprotein, producing massive cholesterol deposition

Goldstein¹,

Basu

et al. 1979

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

2,099

973

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ABSTRACIResident mouse peritoneal macro hages were shown to take up and degrade acetylated 1251 abeled low density lipoprotein (15I-acetyl-LDL) in vitro at rates that were 20fold greater than those for the uptake and degradation of 125I-LDL. The uptake of 1251-acetyl-LDL and its subsequent degradation in lysosomes were attributable to a high-affinity, trypsin-sensitive, surface binding site that recognized acetyl-LDL but not native LDL. When 25I-acetyl-LDL was bound to this site at 4VC and the macrophages were subsequently warmed to 370C, 75% of the cell-bound radioactivity was Studies in cultured human fibroblasts and blood lymphocytes have defined a receptor-mediated pathway by which cells take up and degrade low density lipoprotein (LDL), the major cholesterol-transport protein in human plasma (1, 2). This LDL uptake pathway is believed to function primarily in extrahepatic parenchymal cells where it serves a dual function: it provides the major physiologic route of LDL degradation in the human body and, at the same time, it supplies cholesterol to cells for the synthesis of membranes and steroid hormones.Patients with familial hypercholesterolemia (FH) have a mutation in the gene specifying the LDL receptor (1, 2). In these patients, LDL degradation through the physiologic pathway is blocked, and each LDL particle survives in the circulation 2-3 times longer than it does in normal subjects (3-5). As a result, the lipoprotein accumulates to abnormally high levels in plasma. Eventually the LDL is degraded through an alternate pathway. Inasmuch as the excess LDL-cholesterol becomes deposited in nonparenchymal cells throughout the body, including hepatic Kupffer cells and macrophages of the spleen, kidney, bone marrow, skin, tendons, and other organs (2, 6, 7), we have postulated that the alternate pathway for LDL degradation is expressed primarily in such scavenger cells (2, 5). Because this scavenger mechanism acts on plasma LDL that has circulated for an abnormally long time in vio, it may recognize some form of LDL that has become denatured or chemically modified. The clearance of denatured proteins in vivo by macrophages is well known (8, 9).As a first step in a search for the postulated macrophage system mediating the uptake and degradation of modified or denatured LDL, we have used as a probe 125I-labeled LDL (125I-LDL) that has been extensively acetylated in vitro (125I-acetyl-LDL). The rationale for this choice was based on previous studies showing that acetylation of LDL altered the lipoprotein to the extent that it was no longer recognized by the LDL receptor in fibroblasts (10). As a model cell system for studying the metabolism of '25I-acetyl-LDL, we have used resident mouse peritoneal macrophages isolated by the techniques developed by Cohn and coworkers (11, 12). We demonstrate that these cells possess a high-affinity binding site that recognizes acetyl-LDL but not native LDL. This binding site, which so far appears to occur only on macrophages, mediates the rapid uptake and degradation of acety...

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“…This was first observed by Winter et al 13 in normal dogs and confirmed in that species by Starzl et al, 14 Coyle et al, 15 Horak et al, 16 and Guzman et al 17 The same has been seen in rats, 18,19 pigs, 20,21 and baboons. 12 Studies in the dog 14 and investigations in the rat, 18,22 pig, 20,21 and human 23 have shown or suggested that a reduction in hepatic cholesterol or LDL synthesis or both is responsible at least in part for the falls in cholesterol levels. Only the reports of Coyle et al 15 and Guzman et al 17 in dogs have denied this.…”

Section: Mechanism Of Portal Diversion Effectmentioning

confidence: 99%

Portacaval Shunt and Hyperlipidemia

Starzl¹,

Putnam²,

Koep³

1978

Arch Surg

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Reduction in cholesterol and low density lipoprotein synthesis after portacaval shunt surgery in a patient with homozygous familial hypercholesterolemia.

Cited by 237 publications

References 30 publications

Abnormalities of high density lipoproteins in homozygous familial hypercholesterolemia.

Abnormalities of high density lipoproteins in homozygous familial hypercholesterolemia.

Binding site on macrophages that mediates uptake and degradation of acetylated low density lipoprotein, producing massive cholesterol deposition

Portacaval Shunt and Hyperlipidemia

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