Chylomicron Remnant Metabolism Research Articles

Effect of L-thyroxine replacement on apolipoprotein B-48 in overt and subclinical hypothyroid patients

Apolipoprotein B-48 (ApoB-48) is a constituent of chylomicrons and chylomicron remnants, and is thought to be one of the risk factors for atherosclerosis. We evaluated the effect of L-thyroxine (L-T(4)) replacement on serum ApoB-48 levels in patients with primary hypothyroidism. Eighteen patients with overt hypothyroidism (OH) and 18 patients with subclinical hypothyroidism (SH) participated in the study. The lipid profiles, including ApoB-48, were measured in patients with hypothyroidism before and 3 months after L-T(4) replacement. After L-T(4) replacement, the serum concentrations of all lipoproteins, exclusive of lipoprotein(a) (Lp(a)), were significantly decreased in patients with OH. In patents with SH, the serum levels of total cholesterol (TC), non-high-density lipoprotein cholesterol (non-HDL-C), remnant-like particle cholesterol (RLP-C), apolipoprotein B (ApoB), and ApoB-48 decreased significantly after L-T(4) replacement. The serum levels of triglycerides (TG), HDL-C, low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (ApoA-1), and Lp(a) did not change significantly. In all 36 patients, the reduction in the ApoB-48 levels correlated significantly with the reduction in TSH levels (r = 0.39, P<0.05). This study showed clearly that L-T(4) replacement might reduce serum levels of ApoB-48 in both OH and SH patients. Such altered serum levels of ApoB-48 in patients with OH and SH may be related to the disturbed metabolism of chylomicron remnants in patients with hypothyroidism.

Establishment of chemiluminescence enzyme immunoassay for apolipoprotein B-48 and its clinical applications for evaluation of impaired chylomicron remnant metabolism

BackgroundApolipoprotein B-48 (apoB-48) is a constituent of chylomicron remnants synthesized in the small intestines. The serum concentration of apoB-48 at fasting has been reported to be a marker of postprandial hyperlipidemia, a presumed risk factor for atherosclerosis. MethodsWe evaluated the basal performance of a recently developed chemiluminescent enzyme immunoassay (CLEIA). We also examined the correlations between serum apoB-48 concentrations and other lipid concentrations or life style patterns, including smoking and drinking. We analyzed the data of 273 clinical samples by multiple regression analysis to examine the influence of other serum lipid values, age, sex, smoking, drinking status and BMI on serum apoB-48 values. ResultsWithin-run and between-run precision was obtained with 1.7–2.7% and 1.2–7.3%, respectively. The correlativity of enzyme-linked immunosorbent assay was correlation coefficient r=0.953, and regression y=1.02×−1.59. Serum apoB-48 concentrations were higher in males than in females, and were correlated with the status of smoking as well as with remnant-like particle-cholesterol (RLP-C) concentrations. Patients with the metabolic syndrome showed higher values of serum apoB-48 compared with control subjects. ConclusionSerum apoB-48 measurement by CLEIA was satisfactory for clinical use to assess abnormalities in the chylomicron remnant metabolism.

Does pravastatin increase chylomicron remnant catabolism in postmenopausal women with type 2 diabetes mellitus?

We investigated the effects of pravastatin on chylomicron remnant catabolism measured with a 13C stable isotope breath test and plasma apolipoprotein (apo) B-48 and remnant-like particle (RLP)-cholesterol in postmenopausal women with type 2 diabetes mellitus. Nineteen postmenopausal women with type 2 diabetes were randomized to receive 40 mg/day pravastatin or no treatment for 6 weeks followed by a 2-week washout period, and crossed over for a further 6 weeks. Fractional catabolic rate (FCR) of a chylomicron remnant-like emulsion was determined from 13CO2 enrichment in the breath and plasma using isotope-ratio mass spectrometry and multicompartmental modelling. Plasma apo B-48 and RLP-cholesterol concentrations were also measured as static markers of chylomicron remnant metabolism. Pravastatin significantly reduced plasma concentrations of cholesterol (5.9 +/- 0.3 vs. 4.8 +/- 0.2 mmol/l; P < 0.001), low density lipoprotein (LDL)-cholesterol (3.5 +/- 0.2 vs. 2.6 +/- 0.2 mmol/l; P < 0.001), triglyceride (2.1 +/- 0.3 vs. 1.7 +/- 0.2 mmol/l; P = 0.017), non-high density lipoprotein (HDL)-cholesterol (4.4 +/- 0.3 vs. 3.3 +/- 0.2 mmol/l; P < 0.001), lathosterol/total cholesterol ratio (2.6 +/- 0.2 vs. 2.0 +/- 0.3, P = 0.035), apo B-100 (1.1 +/- 0.1 vs. 0.8 +/- 0.1 g/l; P = 0.001), apo B-48 (4.8 +/- 0.9 vs. 3.3 +/- 0.6 mg/l; P = 0.016), and RLP-cholesterol (31.4 +/- 8.2 vs. 18.6 +/- 4.6 mg/dl; P = 0.024). Pravastatin was also associated with an increase in sitosterol/total cholesterol ratio (2.8 +/- 0.3 vs. 3.1 +/- 0.3, P = 0.029). Chylomicron remnant-like emulsion catabolism was not, however, significantly altered by pravastatin estimated by either breath or plasma clearance measurements. In postmenopausal women, pravastatin decreases plasma concentrations of remnant lipoproteins by a mechanism that may relate chiefly to inhibition of remnant production, but this requires further evaluation.

The apoE isoform binding properties of the VLDL receptor reveal marked differences from LRP and the LDL receptor

Apolipoprotein E (apoE) associates with lipoproteins and mediates their interaction with members of the LDL receptor family. ApoE exists as three common isoforms that have important distinct functional and biological properties. Two apoE isoforms, apoE3 and apoE4, are recognized by the LDL receptor, whereas apoE2 binds poorly to this receptor and is associated with type III hyperlipidemia. In addition, the apoE4 isoform is associated with the common late-onset familial and sporadic forms of Alzheimer's disease. Although the interaction of apoE with the LDL receptor is well characterized, the specificity of other members of this receptor family for apoE is poorly understood. In the current investigation, we have characterized the binding of apoE to the VLDL receptor and the LDL receptor-related protein (LRP). Our results indicate that like the LDL receptor, LRP prefers lipid-bound forms of apoE, but in contrast to the LDL receptor, both LRP and the VLDL receptor recognize all apoE isoforms. Interestingly, the VLDL receptor does not require the association of apoE with lipid for optimal recognition and avidly binds lipid-free apoE. It is likely that this receptor-dependent specificity for various apoE isoforms and for lipid-free versus lipid-bound forms of apoE is physiologically significant and is connected to distinct functions for these receptors.

Scavenger Receptor BI Plays a Role in Facilitating Chylomicron Metabolism

The function of scavenger receptor class B type I (SR-BI) in mediating the selective uptake of high density lipoprotein (HDL) cholesterol esters is well established. However, the potential role of SR-BI in chylomicron and chylomicron remnant metabolism is largely unknown. In the present investigation, we report that the cell association of 160 nm-sized triglyceride-rich chylomicron-like emulsion particles to freshly isolated hepatocytes from SR-BI-deficient mice is greatly reduced (>70%), as compared with wild-type littermate mice. Competition experiments show that the association of emulsion particles with isolated hepatocytes is efficiently competed for (>70%) by the well established SR-BI ligands, HDL and oxidized low density lipoprotein (LDL), whereas LDL is ineffective. Upon injection into SR-BI-deficient mice the hepatic association of emulsion particles is markedly decreased ( approximately 80%) as compared with wild-type mice. The relevance of these findings for in vivo chylomicron (remnant) metabolism was further evaluated by studying the effect of SR-BI deficiency on the intragastric fat load-induced postprandial triglyceride response. The postprandial triglyceride response is 2-fold higher in SR-BI-deficient mice as compared with wild-type littermates (area-under-the-curve 39.6 +/- 1.2 versus 21.1 +/- 3.6; p < 0.005), with a 4-fold increased accumulation of chylomicron (remnant)-associated triglycerides in plasma at 6 h after intragastric fat load. We conclude that SR-BI is important in facilitating chylomicron (remnant) metabolism and might function as an initial recognition site for chylomicron remnants whereby the subsequent internalization can be exerted by additional receptor systems like the LDL receptor and LDL receptor-related protein.

Chylomicron remnant metabolism studied with a new breath test in postmenopausal women with and without type 2 diabetes mellitus

The kinetic basis for the effect of type 2 diabetes mellitus (DM) on postprandial lipoproteins has not been fully established. We investigated chylomicron remnant metabolism using a stable isotope breath test and fasting measurements of plasma apolipoprotein (apo) B-48 and apoC-III concentrations in postmenopausal women with and without type 2 DM. Twenty-four postmenopausal women without DM and 14 postmenopausal women with diet-controlled DM of similar age and body mass index (BMI) were studied in the postabsorptive state. The fractional catabolic rate (FCR) of an intravenously injected chylomicron remnant-like emulsion was determined from the appearance of 13CO2 in the breath using isotope-ratio mass spectrometry and multicompartmental modelling. apoB-48, a marker of particle number of intestinal lipoproteins, was determined immunoelectrophoretically. apoC-III was measured by immunoturbidimetric assay. Compared with the nondiabetic women, the women with DM had significantly higher plasma apoB-48 concentration (16.40 +/- 1.18 mg/l vs. 13.0 +/- 0.9 mg/l; mean +/- standard error mean; P = 0.021), higher plasma apoC-III concentration (204.24 +/- 15.18 mg/l vs. 170.74 +/- 10.75 mg/l; P = 0.042) and lower FCR of the chylomicron remnant-like emulsion (0.06 +/- 0.05 pools/h vs. 0.12 +/- 0.02 pools/h; P < 0.001). In the diabetic patients, the FCR of the emulsion was correlated significantly with plasma apoB-48 levels (r = -0.641, P = 0.007) but not with apoC-III levels. In postmenopausal women, diabetes mellitus appears to decrease the catabolism of chylomicron remnants and result in an accumulation of these particles in plasma. This may chiefly be due to decreased clearance by hepatic receptors related to an effect of insulin resistance. Impairment in the catabolism of chylomicron remnants may contribute to increased risk of atherosclerosis in postmenopausal women with type 2 diabetes mellitus.

Randomized controlled trial of the effect of n–3 fatty acid supplementation on the metabolism of apolipoprotein B-100 and chylomicron remnants in men with visceral obesity

Lipid abnormalities may contribute to the increased risk of atherosclerosis and coronary disease in visceral obesity. Fish oils lower plasma triacylglycerols, but the underlying mechanisms are not fully understood. We studied the effect of fish oils on the metabolism of apolipoprotein B-100 (apo B) and chylomicron remnants in obese men. Twenty-four dyslipidemic, viscerally obese men were randomly assigned to receive either fish oil capsules (4 g/d, consisting of 45% eicosapentaenoic acid and 39% docosahexaenoic acid as ethyl esters) or matching placebo (corn oil, 4 g/d) for 6 wk. VLDL, intermediate-density lipoprotein (IDL), and LDL apo B kinetics were assessed by following apo B isotopic enrichment with the use of gas chromatography-mass spectrometry after an intravenous bolus injection of trideuterated leucine. Chylomicron remnant catabolism was measured with the use of an intravenous injection of a chylomicron remnant-like emulsion containing cholesteryl [(13)C]oleate, and isotopic enrichment of (13)CO(2) in breath was measured with isotope ratio mass spectrometry. Kinetic values were derived with multicompartmental models. Fish oil supplementation significantly (P < 0.05) lowered plasma concentrations of triacylglycerols (-18%) and VLDL apo B (-20%) and the hepatic secretion of VLDL apo B (-29%) compared with placebo. The percentage of conversions of VLDL apo B to IDL apo B, VLDL apo B to LDL apo B, and IDL apo B to LDL apo B also increased significantly (P < 0.05): 71%, 93%, and 11%, respectively. Fish oils did not significantly alter the fractional catabolic rates of apo B in VLDL, IDL, or LDL or alter the catabolism of the chylomicron remnant-like emulsion. Fish oils effectively lower the plasma concentration of triacylglycerols, chiefly by decreasing VLDL apo B production but not by altering the catabolism of apo B-containing lipoprotein or chylomicron remnants.

Randomized controlled trial of the effect of n-3 fatty acids supplementation on apolipoprotein B-100 and chylomicron remnant metabolism in visceral obesity

Randomized controlled trial of the effect of n-3 fatty acids supplementation on apolipoprotein B-100 and chylomicron remnant metabolism in visceral obesity

A factorial study of the effects of atorvastatin and fish oil on chylomicron remnant metabolism studied kinetically with a breath test in obese men

A factorial study of the effects of atorvastatin and fish oil on chylomicron remnant metabolism studied kinetically with a breath test in obese men

Effect of atorvastatin on chylomicron remnant metabolism in visceral obesity: a study employing a new stable isotope breath test

Elevated plasma concentration of chylomicron remnants may be causally related to atherosclerosis in obesity. We examined the effect of atorvastatin on chylomicron remnant metabolism in 25 obese men with dyslipidaemia. A remnant-like emulsion labeled with cholesteryl [13C]oleate was injected intravenously into patients; the fractional catabolic rate (FCR) of the remnant-like emulsion was determined by measurement of 13CO2 in the breath and analyzed using compartmental modelling. Compared with placebo, atorvastatin significantly decreased the plasma concentrations of total cholesterol, triglycerides, LDL cholesterol, apolipoprotein B (apoB), and lathosterol (P < 0.001). ApoB-48 and remnant-like particle-cholesterol (RLP-C) both decreased significantly by 23% (P = 0.002) and 33% (P = 0.045), respectively. The FCR of the remnant-like emulsion increased significantly from 0.054 ± 0.008 to 0.090 ± 0.010 pools/h (P = 0.002). The decrease in RLP-C was associated with the decrease in plasma triglycerides (r = 0.750, P = 0.003). Furthermore, the change in FCR of remnant-like emulsions was inversely associated with the change in LDL-C (r = −0.575, P = 0.040), suggesting removal of LDL and chylomicron remnants by similar hepatic receptor pathways. We conclude that in obese subjects, inhibition of cholesterol synthesis with atorvastatin decreases the plasma concentrations of both LDL-C and triglyceride-rich remnants and that this may be partially due to an enhancement in hepatic clearance of these lipoproteins.—Chan, D. C., G. F. Watts, P. H. R. Barrett, I. J. Martins, A. P. James, J. C. L. Mamo, T. A. Mori, and T. G. Redgrave. Effect of atorvastatin on chylomicron remnant metabolism in visceral obesity: a study employing a new stable isotope breath test. J. Lipid Res. 2002. 43: 706–712.

Food Restriction Normalizes Chylomicron Remnant Metabolism in Murine Models of Obesity as Assessed by a Novel Stable Isotope Breath Test

Evidence is increasing that defective metabolism of postprandial remnants of triglyceride-rich lipoproteins contributes to atherogenesis. In obesity, postprandial lipemia is increased by mechanisms that are not currently established. In the present study, a recently developed (13)CO(2) breath test was used to assess the metabolism of chylomicron remnants (CR) in obese mice. Six murine obese models ob/ob, fat/fat, New Zealand Obese (NZO), db/db, gold thioglucose (GTG)-treated and agouti (A(y)) were studied. All obese mice were hyperphagic and their breath test metabolism was markedly impaired (P < 0.01) compared with control, nonobese mice. The breath test was also impaired (P < 0.01) in all obese mice except A(y) mice after 24-h food deprivation. However, after restriction to the food intake of paired control mice for 6 wk, the breath test in all obese mice improved to values of control, nonobese mice. The obese NZO, fat/fat and ob/ob mice had significant (P < 0.02) weight loss when food restricted, whereas A(y), GTG, and db/db mice did not. In all obese mice, plasma cholesterol levels decreased (P < 0.02) after the 6-wk period of food restriction. Plasma triglyceride levels significantly decreased (P < 0.02) in NZO, GTG and db/db mice, but not in other obese mice. Plasma glucose levels were significantly decreased (P < 0.02) after the 6-wk period in the obese mice except for the A(y) and NZO mice; levels were greater in food-restricted db/db mice. Although some of the obese models such as db/db were diabetic, our data suggest that the defective breath test was independent of diabetes because all obese and diabetic models responded similarly to food restriction. Impaired hepatic catabolism of CR was excluded as a cause of the abnormal breath tests. In summary, the impairment (P < 0.05) in remnant metabolism as assessed by the breath test in obese mice was corrected by food restriction, associated with improvements in plasma glucose, triglyceride and cholesterol levels.

Preliminary experience with a new stable isotope breath test for chylomicron remnant metabolism: a study in central obesity

Preliminary experience with a new stable isotope breath test for chylomicron remnant metabolism: a study in central obesity

Preliminary experience with a new stable isotope breath test for chylomicron remnant metabolism: a study in central obesity.

We aimed to investigate the metabolism of chylomicron remnants in the postabsorptive state employing a new stable isotope breath test in centrally obese men without overt hyperlipidaemia. Groups of 12 centrally obese and 12 non-obese men of similar age and with similar plasma cholesterol and triacylglycerol (triglyceride) levels were studied. The catabolism of chylomicron remnants was measured using an intravenous injection of a remnant-like emulsion containing cholesteryl [(13)C]oleate. Isotopic enrichment of (13)CO(2) in breath was determined using isotope-ratio mass spectrometry, and a multi-compartmental model (SAAM II program) was used to estimate the fractional catabolic rate (FCR) of the chylomicron remnant-like particles. The plasma concentrations of low-density lipoprotein (LDL)-cholesterol, non-high-density lipoprotein (HDL)-cholesterol and insulin were significantly higher (P<0.05) in the obese than the control subjects. The obese subjects had significantly lower HDL-cholesterol (P<0.05) and, in particular, a decreased FCR of the remnant-like particles compared with lean subjects (0.061+/-0.014 and 0.201+/-0.048 pools/h respectively; P=0.016). In the obese group, the FCR of remnant-like particles was inversely associated with the waist/hip ratio, and with plasma triacylglycerol, cholesterol, LDL-cholesterol and non-HDL-cholesterol levels. In multiple regression analysis, the waist/hip ratio was the best predictor of the FCR of the emulsion. In conclusion, this new test suggests that postabsorptive chylomicron remnant catabolism is impaired in centrally obese subjects without overt hyperlipidaemia. This defect may be due to the degree of adiposity.

Chylomicron remnant metabolism in familial hypercholesterolaemia studied with a stable isotope breath test

Chylomicron remnant metabolism was studied using a stable isotope breath test in 25 patients with familial hypercholesterolaemia (FH) (10 homozygotes, 15 heterozygotes), and in 15 normolipidaemic controls. A lipid emulsion mimicking the composition of chylomicron remnants and labelled with cholesteryl 13C-oleate was injected intravenously; 13CO 2 was measured subsequently in breath using isotope-ratio mass spectrometry. The fractional catabolic rate (pools/h) of the emulsion, derived from a compartmental model, did not differ significantly among the groups: homozygous FH mean 0.20 (S.E.M. 0.05), heterozygous FH 0.12 (0.02), controls 0.16 (0.03). We suggest that the catabolism of chylomicron remnants from plasma is not impaired in FH and that the hepatic uptake of these particles is not dependent on functional LDL receptors.

Chylomicron remnant metabolism in familial dyslipidemias studied with a remnant-like emulsion breath test

We have developed a stable isotope breath test for the assessment of chylomicron remnant metabolism and report the results from the breath test in human subjects selected for disorders of chylomicron or remnant metabolism. In type I hyperlipemia, the phenotype is extreme hypertriglyceridemia due to a lack of lipoprotein lipase activity, which causes the failure of remnant formation. The type III dyslipidemia phenotype is caused by the inefficient removal of chylomicron remnants from plasma, generally because of homozygosity for apolipoprotein E2 alleles. The breath test was predicted to be abnormal in type III hyperlipemia, whereas a priori in type I hyperlipemia defective remnant clearance was not anticipated. Subjects were injected with lipid emulsions prepared with a composition similar to normal chylomicron remnants. The emulsions contained cholesteryl ester incorporating the stable nonradioactive isotope 13C in the fatty acid moiety. End exhalation breath was collected at intervals after intravenous injection of the remnant-like emulsions and analyzed for 13C enrichment by isotope-ratio mass spectrometry. Compared with the group of normolipemic men, the fractional catabolic rate of remnants measured by the breath test was significantly decreased (P = 0.006) in subjects with type III dyslipidemia. In the group with type I hyperlipemia, the fractional catabolic rate was not different (P = 0.233) from the control group. Therefore, the underlying capacity for remnant catabolism was normal in this group of markedly hypertriglyceridemic subjects. By short-circuiting the step of lipolysis, the remnant-like emulsion breath test provides direct information about remnant clearance and metabolism, which should assist in investigations of postprandial lipid metabolism.—Redgrave, T. G., G. F. Watts, I. J. Martins, P. H. R. Barrett, J. C. L. Mamo, S. B. Dimmitt, and A. D. Marais. Chylomicron remnant metabolism in familial dyslipidemias studied with a remnant-like emulsion breath test. J. Lipid Res. 2001. 42: 710–715.

Chylomicron remnant metabolism in familial hypercholesterolaemia studied with a stable isotope breath test

Chylomicron remnant metabolism in familial hypercholesterolaemia studied with a stable isotope breath test

Chylomicron remnant metabolism in obese men with and without hypertriglyceridaemia

Chylomicron remnant metabolism in obese men with and without hypertriglyceridaemia

Chylomicron remnant metabolism studied with a new stable isotope breath test in centrally obese subjects

Chylomicron remnant metabolism studied with a new stable isotope breath test in centrally obese subjects

Relative roles of mitochondrial and peroxisomal fatty acid oxidation in the metabolism of chylomicron remnants in rats and mice as assessed by a stable-isotope breath test

We have developed a stable isotope breath test to trace physiological remnant metabolism. Validity of the test depends on the injected lipid emulsion mimicking chylomicron remnant (CR) clearance and on subsequent metabolism of the emulsion cholesteryl ester (CE). Oxidation of CE fatty acids could involve both mitochondrial and peroxisomal pathways. In the present studies various agents were used to inhibit the binding of remnants, CE hydrolysis or mitochondrial fatty acid oxidation. Treatment of mice with suramin or lactoferrin markedly delayed the clearance and metabolism of remnants as shown by the significantly lower enrichment of 13CO 2 in the breath when compared with untreated mice. In hepatectomized rats injected with remnant-like emulsions, enrichment with 13CO 2 was virtually abolished. Treatment of mice with chloroquine or rats with methyl palmoxirate (an inhibitor of mitochondrial fatty acid oxidation) markedly impaired the recovery of label in the breath. Compared with mice fasted overnight, Intralipid by gavage decreased the breath enrichment with 13CO 2 consistent with competition between endogenous CR and the injected emulsion particles. These findings show that the breath test reliably measures the metabolism of CR and that CE fatty acid is metabolised by mitochondrial pathways.

Effect of stanol ester on postabsorptive squalene and retinyl palmitate

Stanol ester dissolved in margarine inhibits cholesterol absorption in general and, despite increasing cholesterol synthesis, decreases serum total and low-density lipoprotein (LDL) cholesterol levels, but its effects on postprandial lipid metabolism are unknown. We performed fat tolerance tests in 11 men at baseline and during short-term stanol ester consumption without and with stanol esters added to the test meal also containing retinol and squalene. Cholesterol, triglycerides, retinyl palmitate, and squalene were analyzed in plasma, chylomicrons, and very-low-density lipoprotein (VLDL) at baseline and 3, 4, 6, 9, 12, and 24 hours after the test meal. Serum total and LDL cholesterol only tended to diminish after the 2-week stanol ester consumption. However, the proportion of plasma plant sterol and cholesterol-precursor sterol to cholesterol was significantly altered, suggesting that cholesterol absorption was diminished and cholesterol synthesis was increased. Postprandial peak times of squalene and retinyl palmitate in plasma, chylomicrons, and VLDL were significantly reduced by stanol esters, but their concentrations in chylomicrons were unchanged. Stanol esters reduced the VLDL squalene peak concentration by 23% (P < .05) and the incremental area under the curve (AUIC) in plasma and VLDL by 22% and 32% (P < .01 for both). Chylomicron remnant metabolism measured with triglycerides only tended to diminish. The effects of stanol esters in the diet only and both in the diet and with supplementation did not differ significantly. We conclude that dietary stanol esters reduce postprandial lipoproteins measured with dietary retinyl palmitate and especially squalene, and the reduction is observed even though serum total and LDL cholesterol are only inconsistently decreased after short-term stanol ester consumption.