Document Detail


Apolipoprotein C-III and the metabolic basis for hypertriglyceridemia and the dense low-density lipoprotein phenotype.
MedLine Citation:
PMID:  20368524     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Here, we aim to identify defects of apolipoprotein (apo) B lipoprotein metabolism that characterize hypertriglyceridemia, focusing on apoC-III and apoE.
METHODS AND RESULTS: We studied the transport of plasma apoB within 21 distinct subfractions as separated by anti-apoC-III and anti-apoE immunoaffinity chromatography and ultracentrifugation in 9 patients with moderate hypertriglyceridemia and 12 normotriglyceridemic control subjects. Hypertriglyceridemia was characterized by a 3-fold higher liver secretion of very low-density lipoprotein (VLDL) that had apoC-III but not apoE and a 50% lower secretion of VLDL with both apoC-III and apoE (both P<0.05). This shift in VLDL secretion pattern from apoE to apoC-III resulted in significantly reduced clearance of light VLDL (-39%; P<0.05), compatible with the antagonizing effects of apoC-III on apoE-induced clearance of triglyceride-rich lipoproteins. In addition, rate constants for clearance were reduced for apoE-containing triglyceride-rich lipoproteins in hypertriglyceridemia, associated with increased apoC-III contents of these particles. LDL distribution shifted from light and medium LDL to dense LDL in hypertriglyceridemia through a quartet of kinetic perturbations: increased flux from apoC-III-containing triglyceride-rich lipoproteins, a shift in liver LDL secretion pattern from light to dense LDL, an increased conversion rate from light and medium LDL to dense LDL, and retarded catabolism of dense LDL.
CONCLUSIONS: These results support a central role for apoC-III in metabolic defects leading to hypertriglyceridemia. Triglyceride-rich lipoprotein metabolism shifts from an apoE-dominated system in normotriglyceridemic participants characterized by rapid clearance from circulation of VLDL to an apoC-III-dominated system in hypertriglyceridemic patients characterized by reduced clearance of triglyceride-rich lipoproteins and the formation of the dense LDL phenotype.
Authors:
Chunyu Zheng; Christina Khoo; Jeremy Furtado; Frank M Sacks
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2010-04-05
Journal Detail:
Title:  Circulation     Volume:  121     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2010 Apr 
Date Detail:
Created Date:  2010-04-20     Completed Date:  2010-05-13     Revised Date:  2014-09-18    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1722-34     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Adult
Apolipoprotein C-III / metabolism*,  secretion
Apolipoproteins B / metabolism,  secretion
Apolipoproteins E / metabolism,  secretion
Cholesterol, VLDL / metabolism
Chromatography, Affinity
Dietary Carbohydrates / administration & dosage
Dietary Fats / administration & dosage
Female
Humans
Hypertriglyceridemia / metabolism*
Leucine / pharmacokinetics
Lipoproteins, LDL / biosynthesis,  metabolism*
Liver / metabolism,  secretion
Male
Middle Aged
Phenotype
Phenylalanine / pharmacokinetics
Triglycerides / metabolism
Grant Support
ID/Acronym/Agency:
P30 DK040561/DK/NIDDK NIH HHS; P30 DK040561-15/DK/NIDDK NIH HHS; R01 HL056210/HL/NHLBI NIH HHS; R01 HL056210-03/HL/NHLBI NIH HHS; R01 HL056210-04/HL/NHLBI NIH HHS; R01 HL056210-05/HL/NHLBI NIH HHS; R01 HL070159/HL/NHLBI NIH HHS; R01 HL070159-01A1/HL/NHLBI NIH HHS; R01 HL070159-02/HL/NHLBI NIH HHS; R01 HL070159-03/HL/NHLBI NIH HHS; R01 HL070159-04/HL/NHLBI NIH HHS; R01-HL-34980/HL/NHLBI NIH HHS; R01-HL-56210/HL/NHLBI NIH HHS; RR02635/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/Apolipoprotein C-III; 0/Apolipoproteins B; 0/Apolipoproteins E; 0/Cholesterol, VLDL; 0/Dietary Carbohydrates; 0/Dietary Fats; 0/Lipoproteins, LDL; 0/Triglycerides; 47E5O17Y3R/Phenylalanine; GMW67QNF9C/Leucine
Comments/Corrections

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