Simultaneous measurement of apolipoprotein B turnover in very-low- and low-density lipoproteins in familial hypercholesterolaemia

Soutar, Anne K.; Myant, N. B.; Thompson, Gilbert R.

doi:10.1016/0021-9150(77)90174-5

Cited by 149 publications

(46 citation statements)

References 13 publications

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“…Alternatively, these lipoproteins may represent abnormal hepatic secretory products. 32 As in human homozygotes, 31 the rate of production of apo B in LDL of WHHL rabbits is severalfold higher than in normal rabbits. 33 The rate of hepatic secretion of VLDL, IDL, or both may be increased as well.…”

Section: Discussionmentioning

confidence: 97%

“…The concentration and rate of production of apo B of VLDL are reportedly normal in humans with homozygous familial hypercholesterolemia, 31 and chylomicron triglyceride catabolism and hepatic uptake of chylomicron cholesteryl esters appear to be unimpaired in WHHL rabbits. 6 However, the concentration of apo B in VLDL and IDL is substantially increased in WHHL rabbits and it is possible that these animals also have a defect in the catabolism of these lipoproteins, perhaps at the level of VLDL remnants.…”

Section: Discussionmentioning

confidence: 99%

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Concentration and composition of lipoproteins in blood plasma of the WHHL rabbit. An animal model of human familial hypercholesterolemia.

et al. 1982

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Concentration and composition of lipoproteins in blood plasma of the WHHL rabbit. An animal model of human familial hypercholesterolemia.

et al. 1982

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“…Two observations have suggested that the LDLR might be involved in apoB secretion. First, overproduction of apoB-containing lipoproteins occurs in some cases of FH (2)(3)(4). Second, drugs that lower LDL levels by increasing the expression of the LDLR (statins) in many instances have been shown to lower LDL without increasing LDL clearance; i.e., they lower LDL and͞or VLDL production (5).…”

Section: Mutations In the Low Density Lipoprotein (Ldl) Receptor (Ldlr)mentioning

confidence: 99%

Endoplasmic reticulum localization of the low density lipoprotein receptor mediates presecretory degradation of apolipoprotein B

Gillian-Daniel

Bates

Tebon

et al. 2002

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

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Mutations in the low density lipoprotein (LDL) receptor (LDLR)cause hypercholesterolemia because of inefficient LDL clearance from the circulation. In addition, there is a paradoxical oversecretion of the metabolic precursor of LDL, very low density lipoprotein (VLDL). We recently demonstrated that the LDLR mediates presecretory degradation of the major VLDL protein, apolipoprotein B (apoB). Kinetic studies suggested that the degradation process is initiated in the secretory pathway. Here, we evaluated the ability of several LDLR variants that are stalled within the secretory pathway to regulate apoB secretion. Both a naturally occurring mutant LDLR and an LDLR consisting of only the ligand-binding domains and a C-terminal endoplasmic reticulum (ER) retention sequence were localized to the ER and not at the cell surface. In the presence of either of the ER-localized LDLRs, apoB secretion was essentially abolished. When the ligand-binding domain of the truncated receptor was mutated the receptor was unable to block apoB secretion, indicating that the inhibition of apoB secretion depends on the ability of the LDLR to bind to its ligand. These findings establish LDLR-mediated pre-secretory apoB degradation as a pathway distinct from reuptake of nascent lipoproteins at the cell surface. The LDLR provides an example of a receptor that modulates export of its ligand from the ER.M olecular defects in the low density lipoprotein (LDL) receptor (LDLR) cause Familial Hypercholesterolemia (FH), a condition associated with elevated plasma LDL cholesterol levels (1). Reduced expression, altered ligand binding, or defective transport to the cell surface all lead to a reduction in the functionally effective population of LDLRs at the cell surface.LDL is produced in the circulation from its precursor, very low density lipoprotein (VLDL). Apolipoprotein B (apoB) is the major protein component of VLDL and LDL. Two observations have suggested that the LDLR might be involved in apoB secretion. First, overproduction of apoB-containing lipoproteins occurs in some cases of FH (2-4). Second, drugs that lower LDL levels by increasing the expression of the LDLR (statins) in many instances have been shown to lower LDL without increasing LDL clearance; i.e., they lower LDL and͞or VLDL production (5).The proportion of apoB that escapes degradation within the secretory pathway primarily determines the rate of VLDL secretion. We recently demonstrated that the presence of the LDLR greatly increases the proportion of apoB subject to presecretory degradation. Our results directly link VLDL overproduction in FH with the loss of the LDLR (6).Several additional studies support a role for the LDLR in modulating apoB secretion. Increased secretion of VLDL is observed in vivo from both Ldlr Ϫ/Ϫ and transgenic Ldlr Ϫ/Ϫ mice that overexpress the nuclear form of sterol regulatory element binding protein-1a (SREBP-1a) and in vitro in hepatocytes from these animals (7). In contrast, transgenic SREBP-1a animals with a wild-type LDLR accumulate cholesterol a...

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“…Soutar et al 154 found no change in LDL synthesis and an actual rise in very-low-density lipoprotein (VLDL) synthesis in the patient discussed earlier whose shunt may have closed. Strikingly different conclusions were reached after metabolic studies in three of the 12 patients of our own series.…”

Section: Experience Of Others In Treating Fh-mentioning

confidence: 95%

“…20,158 In two of the three exceptional patients, shunt thrombosis was proved, 151,152 and in one of these the cholesterol level fell by 40% after a later mesocaval shunt. 152 In the third patient, described by Soutar, My ant, and Thompson,154 there was presumptive but not definitive evidence of shunt occlusion. The cholesterol level, after an early fall of 40%, returned several months later to near preoperative values.…”

Section: Experience Of Others In Treating Fh-mentioning

confidence: 97%

The ECK fistula in animals and humans

Starzl¹

1983

Current Problems in Surgery

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Simultaneous measurement of apolipoprotein B turnover in very-low- and low-density lipoproteins in familial hypercholesterolaemia

Cited by 149 publications

References 13 publications

Concentration and composition of lipoproteins in blood plasma of the WHHL rabbit. An animal model of human familial hypercholesterolemia.

Concentration and composition of lipoproteins in blood plasma of the WHHL rabbit. An animal model of human familial hypercholesterolemia.

Endoplasmic reticulum localization of the low density lipoprotein receptor mediates presecretory degradation of apolipoprotein B

The ECK fistula in animals and humans

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