Abstract 236: Lipoprotein Metabolism in APOB L343V Familial Hypobetalipoproteinemia

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Amanda J Hooper ◽  
Ken Robertson ◽  
Liesl V Heeks ◽  
Danie Champain ◽  
P Hugh R Barrett ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Lipoprotein Metabolism ◽  
Compartmental Modeling ◽  
Apo B ◽  
Control Subjects ◽  
Modeling Analysis ◽  
Catabolic Rate ◽  
Postprandial Lipoprotein ◽  
Familial Hypobetalipoproteinemia

Familial hypobetalipoproteinemia (FHBL) is a codominant disorder of lipoprotein metabolism characterized by decreased plasma concentrations of LDL-cholesterol and apolipoprotein (apo) B. We examined the effect of heterozygous APOB L343V FHBL on fasting and postprandial lipoprotein metabolism. VLDL, IDL-, and LDL-apoB kinetics were determined in the fasting state using stable isotope methods and compartmental modeling. VLDL-apoB concentrations in FHBL subjects (n=2) were reduced by more than 75% compared to healthy, normolipidemic control subjects ( P <0.01). VLDL-apoB fractional catabolic rate (FCR) was more than 5-fold higher in the FHBL subjects ( P =0.07). ApoB production rates and IDL- and LDL-apoB FCRs were not different between FHBL subjects and controls. To assess postprandial lipoprotein metabolism, a standardized oral fat load was given after a 12 h fast to heterozygous APOB L343V FHBL subjects (n=3) and normolipidemic controls. The postprandial incremental area under the curve (0-10 h) in FHBL subjects was decreased for large TRL-triglyceride (-77%; P <0.0001), small TRL-cholesterol (-83%; P <0.001), small TRL-triglyceride (-88%; P <0.0.001) and plasma apoB (-63%; P <0.0001) compared with controls. Compartmental modeling analysis showed that apoB-48 production was decreased (-91%; P <0.05) compared with controls. We conclude that when compared to controls, APOB L343V FHBL heterozygotes show decreased TRL production with normal postprandial TRL particle clearance. In contrast, VLDL-apoB production was normal, while the FCR was higher in heterozygotes compared with lean control subjects. These mechanisms account for the marked hypolipidemic state observed in these FHBL subjects.

scholarly journals Lipoprotein Metabolism in APOB L343V Familial Hypobetalipoproteinemia

2015 ◽  
Vol 100 (11) ◽  
pp. E1484-E1490 ◽  
Author(s):  
Amanda J. Hooper ◽  
Liesl Heeks ◽  
Ken Robertson ◽  
Danie Champain ◽  
Jianmin Hua ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Lipoprotein Metabolism ◽  
Density Lipoprotein ◽  
Compartmental Modeling ◽  
Low Density ◽  
Control Subjects ◽  
Postprandial Triglyceride ◽  
Familial Hypobetalipoproteinemia

Context: Familial hypobetalipoproteinemia (FHBL) is a codominant disorder of lipoprotein metabolism characterized by decreased plasma concentrations of low-density lipoprotein (LDL)-cholesterol and apolipoprotein B (apoB). Objective: The objective was to examine the effect of heterozygous APOB L343V FHBL on postprandial triglyceride-rich lipoprotein (TRL) and fasting lipoprotein metabolism. Methods: Plasma incremental area under the curve apoB-48 and apoB-48 kinetics were determined after ingestion of a standardized oral fat load using compartmental modeling. Very low-density lipoprotein (VLDL)-, intermediate-density lipoprotein (IDL)-, and LDL-apoB kinetics were determined in the fasting state using stable isotope methods and compartmental modeling. Results: The postprandial incremental area under the curve (0–10 h) in FHBL subjects (n = 3) was lower for large TRL-triglyceride (−77%; P &lt; .0001), small TRL-cholesterol (−83%; P &lt; .001), small TRL-triglyceride (−88%; P &lt; .001), and for plasma triglyceride (−70%; P &lt; .01) and apoB (−63%; P &lt; .0001) compared with controls. Compartmental analysis showed that apoB-48 production was lower (−91%; P &lt; .05) compared with controls. VLDL-apoB concentrations in FHBL subjects (n = 2) were lower by more than 75% compared with healthy, normolipidemic control subjects (P &lt; .01). The VLDL-apoB fractional catabolic rate (FCR) was more than 5-fold higher in the FHBL subjects (P = .07). ApoB production rates and IDL- and LDL-apoB FCRs were not different between FHBL subjects and controls. Conclusions: We conclude that when compared to controls, APOB L343V FHBL heterozygotes show lower TRL production with normal postprandial TRL particle clearance. In contrast, VLDL-apoB production was normal, whereas the FCR was higher in heterozygotes compared with lean control subjects. These mechanisms account for the marked hypolipidemic state observed in these FHBL subjects.

scholarly journals Assessment of Tocopherol Metabolism and Oxidative Stress in Familial Hypobetalipoproteinemia

2006 ◽  
Vol 52 (7) ◽  
pp. 1339-1345 ◽  
Author(s):  
Michael W Clarke ◽  
Amanda J Hooper ◽  
Henrietta A Headlam ◽  
Jason HY Wu ◽  
Kevin D Croft ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Vitamin E ◽  
Ldl Cholesterol ◽  
Plasma Concentrations ◽  
Lipoprotein Metabolism ◽  
Gas Chromatography Mass Spectrometry ◽  
Apo B ◽  
Familial Hypobetalipoproteinemia ◽  
And Oxidative Stress ◽  
Vitamin E Supplementation

Abstract Background: Vitamin E supplementation has been recommended for persons with familial hypobetalipoproteinemia (FHBL), a rare disorder of lipoprotein metabolism that leads to low serum α-tocopherol and decreased LDL-cholesterol and apolipoprotein (apo) B. We examined the effect of truncated apoB variants on vitamin E metabolism and oxidative stress in persons with FHBL. Methods: We studied 9 individuals with heterozygous FHBL [mean (SE) age, 40 (5) years; body mass index (BMI), 27 (10) kg/m2] and 7 normolipidemic controls [age, 41 (5) years; BMI, 25 (2) kg/m2]. We also studied 3 children—2 with homozygous FHBL (apoB-30.9) and 1 with abetalipoproteinemia—who were receiving α-tocopherol supplementation. We used HPLC with electrochemical detection to measure α- and γ-tocopherol in serum, erythrocytes, and platelets, and gas chromatography–mass spectrometry to measure F2-isoprostanes and tocopherol metabolites in urine as markers of oxidative stress and tocopherol intake, respectively. Results: Compared with controls, persons with FHBL had significantly lower fasting plasma concentrations of total cholesterol [2.4 (0.2) vs 4.7 (0.2) mmol/L], triglycerides [0.5 (0.1) vs 0.9 (0.1) mmol/L], LDL-cholesterol [0.7 (0.1) vs 2.8 (0.3) mmol/L], apoB [0.23 (0.02) vs 0.84 (0.08) g/L], α-tocopherol [13.6 (1.0) vs 28.7 (1.4) μmol/L], and γ-tocopherol [1.0 (0.1) vs 1.8 (0.3) μmol/L] (all P &lt;0.03). Erythrocyte α-tocopherol was decreased [5.0 (0.2) vs 6.0 (0.3) μmol/L; P &lt;0.005], but we observed no differences in lipid-adjusted serum tocopherols, erythrocyte γ-tocopherol, platelet α- or γ-tocopherol, urinary F2-isoprostanes, or tocopherol metabolites. Conclusion: Taken together, our findings do not support the recommendation that persons with heterozygous FHBL receive vitamin E supplementation.

scholarly journals Liver Dysfunction and Steatosis in Familial Hypobetalipoproteinemia

2005 ◽  
Vol 51 (1) ◽  
pp. 266-269 ◽  
Author(s):  
Amanda J Whitfield ◽  
P Hugh R Barrett ◽  
Ken Robertson ◽  
Marek F Havlat ◽  
Frank M van Bockxmeer ◽  
...  
Keyword(s):  
Fatty Liver ◽  
Liver Dysfunction ◽  
Hereditary Hemochromatosis ◽  
Plasma Concentrations ◽  
Iron Concentration ◽  
Transferrin Saturation ◽  
Unique Case ◽  
Apo B ◽  
Familial Hypobetalipoproteinemia ◽  
Alanine Aminotransferase Activity

Abstract A 32-year-old man presented with increases in serum alanine aminotransferase activity, iron concentration, and transferrin saturation, suggestive of hepatic dysfunction and iron overload. In addition, he had unusually low plasma concentrations of LDL-cholesterol and apolipoprotein (apo) B. Hepatic ultrasonography was consistent with fatty liver. On liver biopsy, marked steatosis and moderate to marked iron deposition were observed. The patient was found to carry the HFE C282Y and H63D mutations, which are associated with hereditary hemochromatosis, and the α1-antitrypsin PiZ variant. An immunoblot of plasma for apoB showed the presence of a truncated apoB species, indicative of familial hypobetalipoproteinemia. DNA sequence analysis revealed that the patient was heterozygous for the apoB-80.5 (c.11040T&gt;G) mutation. This unique case shows an unusual combination of underlying disorders that could all be contributing to liver dysfunction and fatty liver.

scholarly journals Lipoprotein(a) in the Nephrotic Syndrome

2000 ◽  
Vol 11 (3) ◽  
pp. 507-513
Author(s):  
CHANTAL DOUCET ◽  
VINCENT MOOSER ◽  
SOPHIE GONBERT ◽  
FRANÇOISE RAYMOND ◽  
JOHN CHAPMAN ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Plasma Concentrations ◽  
Lipoprotein A ◽  
Control Subjects ◽  
Large N ◽  
Catabolic Rate ◽  
Atherogenic Particle ◽  
Normal Urine ◽  
And Control

Abstract. Plasma levels of lipoprotein(a) (Lp(a)), an atherogenic particle, are elevated in kidney disease, which suggests a role of this organ in the metabolism of Lp(a). Additional evidence for a role of the kidney in the clearance of Lp(a) is provided by the fact that circulating N-terminal fragments of apolipoprotein(a) (apo(a)) are processed and eliminated by the renal route. To further understand the mechanism underlying such renal excretion, the levels of apo(a) fragments in plasma and urine relative to plasma Lp(a) levels were determined in patients with nephrotic syndrome (n = 15). In plasma, the absolute (24.7 ± 20.4 versus 2.16 ± 2.99 μg/ml, P < 0.0001) as well as the relative amounts of apo(a) fragments (4.6 ± 3.4% versus 2.1 ± 3.3% of total Lp(a), P < 0.0001) were significantly elevated in nephrotic patients compared with a control, normolipidemic population. In addition, urinary apo(a) excretion in patients with nephrotic syndrome was markedly elevated compared with that in control subjects (578 ± 622 versus 27.7 ± 44 ng/ml per mg creatinine, P < 0.001). However, the fractional catabolic rates of apo(a) fragments were similar in both groups (0.68 ± 0.67% and 0.62 ± 0.47% in nephrotic and control subjects, respectively), suggesting that increased plasma concentrations of apo(a) fragments in nephrotic subjects are more dependent on the rate of synthesis rather than on the catabolic rate. Molecular analysis of apo(a) immunoreactive material in urine revealed that the patterns of apo(a) fragments in nephrotic patients were distinct from those of control subjects. Full-length apo(a), large N-terminal apo(a) fragments similar in size to those present in plasma, as well as C-terminal fragments of apo(a) were detected in urine from nephrotic patients but not in urine from controls. All of these apo(a) forms were in addition to smaller N-terminal apo(a) fragments present in normal urine. This study also demonstrated the presence of Lp(a) in urine from nephrotic patients by ultracentrifugal fractionation. These data suggest that in nephrotic syndrome, Lp(a) and large fragments of apo(a) are passively filtered by the kidney through the glomerulus, whereas smaller apo(a) fragments are secreted into the urine.

scholarly journals Lipid Disorders and Mutations in the APOB Gene

2004 ◽  
Vol 50 (10) ◽  
pp. 1725-1732 ◽  
Author(s):  
Amanda J Whitfield ◽  
P Hugh R Barrett ◽  
Frank M van Bockxmeer ◽  
John R Burnett
Keyword(s):  
Ldl Receptor ◽  
Lipoprotein Metabolism ◽  
Plasma Lipoproteins ◽  
Premature Coronary Artery Disease ◽  
Missense Mutations ◽  
Apob Gene ◽  
Apo B ◽  
Ldl Particles ◽  
Genetic Features ◽  
Familial Hypobetalipoproteinemia

Abstract Background: Plasma lipoproteins are important determinants of atherosclerosis. Apolipoprotein (apo) B is a large, amphipathic glycoprotein that plays a central role in human lipoprotein metabolism. Two forms of apoB are produced from the APOB gene by a unique posttranscriptional editing process: apoB-48, which is required for chylomicron production in the small intestine, and apoB-100, required for VLDL production in the liver. In addition to being the essential structural component of VLDL, apoB-100 is the ligand for LDL-receptor-mediated endocytosis of LDL particles. Content: The study of monogenic dyslipidemias has revealed important aspects of metabolic pathways. In this review, we discuss the regulation of apoB metabolism and examine how APOB gene defects can lead to both hypo- and hypercholesterolemia. The key clinical, metabolic, and genetic features of familial hypobetalipoproteinemia and familial ligand-defective apoB-100 are described. Summary: Missense mutations in the LDL-receptor-binding domain of apoB cause familial ligand-defective apoB-100, characterized by hypercholesterolemia and premature coronary artery disease. Other mutations in APOB can cause familial hypobetalipoproteinemia, characterized by hypocholesterolemia and resistance to atherosclerosis. These naturally occurring mutations reveal key domains in apoB and demonstrate how monogenic dyslipidemias can provide insight into biologically important mechanisms.

scholarly journals Markers of Triglyceride-rich Lipoprotein Remnant Metabolism in Visceral Obesity

2002 ◽  
Vol 48 (2) ◽  
pp. 278-283 ◽  
Author(s):  
Dick C Chan ◽  
Gerald F Watts ◽  
P Hugh Barrett ◽  
John CL Mamo ◽  
Trevor G Redgrave
Keyword(s):  
Insulin Resistance ◽  
Polyacrylamide Gel Electrophoresis ◽  
Plasma Concentrations ◽  
Sodium Dodecyl ◽  
Visceral Obesity ◽  
Hdl Cholesterol ◽  
Isotope Ratio Mass Spectrometry ◽  
Apo B ◽  
Catabolic Rate ◽  
Triglyceride Rich Lipoprotein

Abstract Background: Triglyceride-rich lipoprotein remnants are atherogenic, and this may be particularly important in visceral obesity. We investigated remnant metabolism in obese men by measuring remnant-like particle-cholesterol (RLP-C), apolipoprotein (apo) B-48, apoC-III, and the clearance of a labeled remnant-like emulsion. Methods: Fasting RLP-C, apoB-48, and apoC-III concentrations were measured in 48 viscerally obese men and 10 lean controls. RLP-C was determined by immunoseparation assay, apoB-48 by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and enhanced chemiluminescence, and apoC-III by immunoturbidimetric assay. The catabolism of chylomicron remnants was measured by intravenous injection of a remnant-like emulsion containing cholesteryl [13C]oleate, with isotopic enrichment of 13CO2 in breath determined by isotope-ratio mass spectrometry and a multicompartmental model to estimate fractional catabolic rate (FCR) of the emulsion. Results: Compared with controls, obese men had significantly increased plasma concentrations of RLP-C, apoB-48, and apoC-III (P &lt;0.001 for all). Plasma total apoB-100, non-HDL-cholesterol, LDL-cholesterol, triglycerides, and insulin resistance (HOMA score) were also significantly higher in the obese group (P &lt;0.001 for all). Obese men had a significantly lower FCR of the remnant-like emulsion compared with controls (P = 0.020). Conclusions: Viscerally obese individuals have insulin resistance and increased plasma concentrations of triglyceride-rich lipoprotein remnants, which may be attributable to decreased catabolism of these particles.

scholarly journals Postprandial Lipoprotein Metabolism in Familial Hypobetalipoproteinemia

2007 ◽  
Vol 92 (4) ◽  
pp. 1474-1478 ◽  
Author(s):  
Amanda J. Hooper ◽  
Ken Robertson ◽  
P. Hugh R. Barrett ◽  
Klaus G. Parhofer ◽  
Frank M. van Bockxmeer ◽  
...  
Keyword(s):  
Lipoprotein Metabolism ◽  
Postprandial Lipoprotein ◽  
Familial Hypobetalipoproteinemia

Design, Synthesis, Anticonvulsant Activity, Preclinical Study and Pharmacokinetic Performance of N-{[3-(4-chlorophenyl)-4-oxo-3, 4-dihydroquinazolin- 2-yl] methyl}, 2-[(2-isopropyl-5-methyl) 1-cyclo Hexylidene] Hydrazinecarboxamide

2019 ◽  
Vol 19 (1) ◽  
pp. 31-45
Author(s):  
Meena K. Yadav ◽  
Laxmi Tripathi
Keyword(s):  
Anticonvulsant Activity ◽  
Computational Study ◽  
Plasma Concentrations ◽  
Elimination Rate ◽  
Area Under The Curve ◽  
Preclinical Study ◽  
In Vivo Studies ◽  
Maximum Plasma ◽  
Seizure Models

Background: N-{[3-(4-chlorophenyl)-4-oxo-3, 4-dihydroquinazolin-2-yl] methyl}, 2-[(2- isopropyl-5-methyl) 1-cyclohexylidene] hydrazinecarboxamide QS11 was designed by computational study. It possessed essential pharmacophoric features for anticonvulsant activity and showed good docking with iGluRs (Kainate) glutamate receptor. Methods: QSAR and ADMET screening results suggested that QS11 would possess good potency for anticonvulsant activity. QS11 was synthesised and evaluated for its anticonvulsant activity and neurotoxicity. QS11 showed protection in strychnine, thiosemicarbazide, 4-aminopyridine and scPTZ induced seizure models and MES seizure model. QS11 showed higher ED50, TD50 and PI values as compared to the standard drugs in both MES and scPTZ screen. A high safety profile (HD50/ED50 values) was noted and hypnosis, analgesia, and anaesthesia were only observed at higher doses. No considerable increase or decrease in the concentration of liver enzymes was observed. Optimized QS11 was subjected to preclinical (in-vivo) studies and the pharmacokinetic performance of the sample was investigated. The result revealed that the pharmacokinetic performance of QS11 achieved maximum plasma concentrations (Cmax) of 0.315 ± 0.011 µg/mL at Tmax of 2.0 ± 0.13 h, area under the curve (AUC0-∞) value 4.591 ± 0.163 µg/ml x h, elimination half-life (T1/2) 6.28 ± 0.71 h and elimination rate constant was found 0.110 ± 0.013 h-1. Results and Conclusion: Above evidences indicate that QS11 could serve as a lead for development of new antiepileptic drugs.

scholarly journals Physiologically Based Pharmacokinetic Modelling of Cabozantinib to Simulate Enterohepatic Recirculation, Drug–Drug Interaction with Rifampin and Liver Impairment

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 778
Author(s):  
Bettina Gerner ◽  
Oliver Scherf-Clavel
Keyword(s):  
Hepatic Impairment ◽  
Kinase Inhibitor ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Enterohepatic Recirculation ◽  
Maximum Plasma ◽  
Good Precision ◽  
Physiologically Based Pharmacokinetic ◽  
Starting Point ◽  
Physiologically Based

Cabozantinib (CAB) is a receptor tyrosine kinase inhibitor approved for the treatment of several cancer types. Enterohepatic recirculation (EHC) of the substance is assumed but has not been further investigated yet. CAB is mainly metabolized via CYP3A4 and is susceptible for drug–drug interactions (DDI). The goal of this work was to develop a physiologically based pharmacokinetic (PBPK) model to investigate EHC, to simulate DDI with Rifampin and to simulate subjects with hepatic impairment. The model was established using PK-Sim® and six human clinical studies. The inclusion of an EHC process into the model led to the most accurate description of the pharmacokinetic behavior of CAB. The model was able to predict plasma concentrations with low bias and good precision. Ninety-seven percent of all simulated plasma concentrations fell within 2-fold of the corresponding concentration observed. Maximum plasma concentration (Cmax) and area under the curve (AUC) were predicted correctly (predicted/observed ratio of 0.9–1.2 for AUC and 0.8–1.1 for Cmax). DDI with Rifampin led to a reduction in predicted AUC by 77%. Several physiological parameters were adapted to simulate hepatic impairment correctly. This is the first CAB model used to simulate DDI with Rifampin and hepatic impairment including EHC, which can serve as a starting point for further simulations with regard to special populations.

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