Kinetic bases of the primar hperlipidaemias: studies of apolipoprotein B turnover in geneticall defined subjects

Janus, Edward; Nicoll, A.; Turner, Peter R.; Magill, Peter J.; Lewis, Barry

doi:10.1111/j.1365-2362.1980.tb02076.x

Cited by 249 publications

(83 citation statements)

References 39 publications

(8 reference statements)

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“…This latter disorder is manifested by elevated cholesterol, TG, or both, and by multiple lipoprotein phenotypes in the same family. 303233 Those with elevated LDL almost certainly have excessive synthesis of LDL apo B as well, 31 and overproduction of apo B may be the fundamental metabolic defect in this disorder. Familial combined hyperiipidemia confers an increased risk of CHD regardless of lipoprotein phenotype; 20 21 this greater risk is present even in those with high VLDL and normal LDL.…”

Section: Discussionmentioning

confidence: 99%

Overproduction of low density lipoproteins associated with coronary heart disease.

Ya¹,

Grundy²

1983

Arteriosclerosis

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The turnover rates of low density lipoprotein-apolipoprotein (apoLDL) were determined in eight men with coronary heart disease (CHD) and seven men matched for age, weight, and plasma lipid levels who were used for controls. The CHD patients were normocholesterolemic (plasma cholesterol = 204 ± 8 mg/dl SEM) as were the control subjects (227 ±15 mg/dl). The concentrations of plasma LDL cholesterol and apoLDL were similar for the two groups. In contrast, the synthetic rates of apoLDL were higher in the CHD patients (20.0 ± 1.8 mg/kg/day) than in the controls (12.9 ± 1.1 mg/kg/day) (p < 0.01). The ratios of protein-to-cholesterol in LDL averaged 19% higher in the CHD patients. These patients with CHD maintained normal LDL levels despite an over-production of apoLDL because of an increased capacity for LDL removal; their fractional catabolic rates of apoLDL averaged 43% higher than those of the controls. These findings indicate that some patients with CHD have abnormalities in the turnover of apoLDL, even with normal concentrations of LDL; these abnormalities may contribute to accelerated atherosclerosis. (Arteriosclerosis 3:40-46, January/February 1983) E levated levels of total plasma cholesterol and the major cholesterol-carrying lipoprotein, low density lipoprotein (LDL), are associated with increased risk for coronary heart disease (CHD).12 However, concentrations of plasma total and LDL cholesterol overlap considerably among people with and without premature CHD. Recently, high levels of LDL apolipoprotein B (apo B) have been reported to separate patients with CHD from unaffected people better than do total cholesterol, triglycerides (TG), or LDL cholesterol.3 In this same report, patients were described who had advanced atherosclerosis, elevated LDL apo B, but normal LDL cholesterol. Thus, abnormalities in metabolism of LDL apo B, which may not be reflected in LDL cholesterol concentrations, could contribute to atherosclerosis. To examine this possi- bility further, we undertook this study to determine the production and removal of LDL protein (apoLDL, which is over 90% apo B) in patients with CHD and in control patients matched for age, sex, and plasma lipid concentrations. Methods PatientsEight men with well-documented CHD and seven healthy men (controls) were studied (table 1). At the time of the study, the CHD patients were 60 ± 3 years old (SEM) (an age range of 49 to 71 years) and their ages at the clinical onset of CHD averaged 51 ± 3 years (from 43 to 66 years). Their mean body weight was 74 ± 2 kg (mean ideal weight = 108 ± 3%). In six patients, coronary artery bypass grafting was done an average of 6 years after the onset of CHD. The two patients without grafts had had previous myocardial infarctions proven by electrocardiograms and enzyme changes. Many patients had bruits over carotid and femoral arteries, but none had clinical heart failure. Also, none had xanthomata, xanthelasma, fasting or 2-hour postprandial hyperglycemia. Four patients (Nos. 1, 2, 3, and 4) were taking propranolol for hypertens...

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Section: Discussionmentioning

confidence: 99%

Overproduction of low density lipoproteins associated with coronary heart disease.

Ya¹,

Grundy²

1983

Arteriosclerosis

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“…Indeed, Chait et al, 27 Janus et al, 28 and Kissebah et al, 29 have presented data indicating that patients with FCHL have overproduction of VLDL-apo B. Perhaps a primary increase in the synthesis of apo B could stimulate the formation of excess VLDL-TG.…”

Section: Familial Combined Hyperlipidemiamentioning

confidence: 99%

“…To correct for losses of neutral steroids, beta-sitosterol was given as capsules (225 mg twice daily), 25 and excretions of acidic steroids were corrected for variations in fecal flow by use of chromic oxide. 28 For control, 14 normal men were studied for 1 month on the same dietary regimen and by the same analytic techniques. The ages of the controls ranged from 29 to 63 years (mean, 51 years); their weights were 95% to 115% of ideal.…”

Section: Cholesterol Balance Studiesmentioning

confidence: 99%

Triglyceride and cholesterol metabolism in primary hypertriglyceridemia.

Beil¹,

Grundy²,

Crouse³

et al. 1982

Arteriosclerosis

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To determine mechanisms of elevated plasma trlglycerldes (TG) in patients with primary hypertrlglyceridemlas, simultaneous studies were carried out on kinetics of very low density llpoproteln-triglycerides (VLDL-TG) and synthesis of cholesterol and bile acids. Sixteen hypertrlglyceridemlc patients with familial combined hyperllpldemla (FCHL) and 12 patients with poorly classified, primary hypertriglyceridemia were studied, and their results were compared to a series of normal and obese subjects previously studied In our laboratory. The mean value for transport (synthesis) of VLDL-TG in patients with FCHL was about twice normal. Although the upper normal synthesis rates overlapped with transport rates of some patients with FCHL, It appeared that the major cause of hypertriglyceridemia in FCHL was an elevated production of VLDL-TG. However, the height of the plasma TG in FCHL patients also was influenced by Individual clearance capacities for VLDL-TG, and fractional clearance rates In several seemed particularly low. Synthesis rates for cholesterol and/or bile acids were high In several patients with FCHL, suggesting simultaneous overproduction of VLDL-TG and sterols; however, Increased synthesis of both was not observed In all the patients. Most patients with poorly classified hypertriglyceridemia had overproduction of VLDL-TG, but an apparent reduction in clearance was common. In these patients, Increased synthesis of cholesterol and bile acids was Infrequent. Our results indicate that abnormally high production of VLDL-TG seemed to be the major factor In causing primary hypertriglyceridemia, but that clearance capacity can play an important role In determining the severity of the TG elevation. (Arteriosclerosis 2:44-57, January/February 1982)

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“…For experiments, cells were plated out at a density of 1.3xlO 4 12 Tissue-culture medium was purchased from Flow Laboratories (MacLean, Va.).…”

Section: +mentioning

confidence: 99%

Pathogenesis of carbohydrate-induced hypertriglyceridemia using HepG2 cells as a model system.

Cianflone

Dahan

Monge

et al. 1992

Arterioscler Thromb

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This study compares the effects of glucose and fatty acid on hepatic lipid synthesis and apolipoproteln (apo) B secretion. To do so, varying concentrations of either glucose or oleic acid were added to the medium in which HepG2 cells were being incubated. Intracellular triacylglycerol and cholesteryl ester synthesis and secretion were measured by addition of radioisotopic tracers and by determination of mass, whereas apo B concentration in the medium was measured by a specific enzyme-linked immunosorbent assay. The data indicate that increasing concentrations of glucose in the medium resulted in increased synthesis of triacylglycerol within the cell and increased secretion of triacylglycerol into the medium. Apo B secretion into the medium, however, did not change, and intracellular synthesis and secretion of cholesteryl ester did not change as well. By contrast, addition of oleic acid to the medium resulted in increased synthesis and secretion of both cholesteryl ester and triacylglycerol, and this was associated with increased secretion of apo B into the medium. Thus, a carbohydrate load resulted in secretion of normal numbers of triacylgtycerol-enriched apo B particles by this hepatocyte cell line, whereas a fatty acid load led to the secretion of increased numbers of apo B particles, which were essentially normal in composition. 1 -2 It is obviously, therefore, not a unitary entity. Two different clearance defects have been recognized: the first involves the rate of triacylglycerol hydrolysis (lipoprotein lipase and apolipoprotein [apo] CH deficiency fall in this category 1 ), whereas the second involves impaired removal of chylomicron and very low density lipoprotein (VLDL) remnants (with type III hyperlipoproteinemia being the prototype of this class of disorders).3 Two different genetic forms of hepatic overproduction of VLDL have also been recognized: familial hypertriglyceridemia and familial combined hyperlipidemia. The former is characterized by the secretion of normal numbers of triacylglycerol-enriched VLDL particles, whereas the latter is characterized by secretion of increased numbers of VLDL particles of normal composition. 4 -6 However, little is yet known of the processes that regulate VLDL secretion. Almost all available in vitro evidence supports the view that apo B production rates are modulated by posttranslational mechanisms, 7 -8 and we have advanced the hypothesis that cholesteryl ester synthesis is critical in this regard, at least so far as the response to increased delivery of fatty acids to the liver is concerned. 9 Nevertheless, it has been well documented that carbohydrate feeding also can lead to increased plasma triacylglycerols, 1011 presumably through increased delivery of glucose to the liver. Accordingly, the present studies were undertaken to compare the response of HepG2 cells on the one hand to an exogenous glucose load and, on the other, to an exogenous fatty acid load. Our expectation was that the latter would result in secretion of increased numbers of apo B partic...

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Kinetic bases of the primar hperlipidaemias: studies of apolipoprotein B turnover in geneticall defined subjects

Cited by 249 publications

References 39 publications

Overproduction of low density lipoproteins associated with coronary heart disease.

Overproduction of low density lipoproteins associated with coronary heart disease.

Triglyceride and cholesterol metabolism in primary hypertriglyceridemia.

Pathogenesis of carbohydrate-induced hypertriglyceridemia using HepG2 cells as a model system.

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