Document Detail


Functional analysis of the missense APOC3 mutation Ala23Thr associated with human hypotriglyceridemia.
MedLine Citation:
PMID:  20097930     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We have shown that expression of apolipoprotein (apo) C-III promotes VLDL secretion from transfected McA-RH7777 cells under lipid-rich conditions. To determine structural elements within apoC-III that confer to this function, we contrasted wild-type apoC-III with a mutant Ala23Thr originally identified in hypotriglyceridemia subjects. Although synthesis of [(3)H]glycerol-labeled TAG was comparable between cells expressing wild-type apoC-III (C3wt cells) or Ala23Thr mutant (C3AT cells), secretion of [(3)H]TAG from C3AT cells was markedly decreased. The lowered [(3)H]TAG secretion was associated with an inability of C3AT cells to assemble VLDL(1). Moreover, [(3)H]TAG within the microsomal lumen in C3AT cells was 60% higher than that in C3wt cells, yet the activity of microsomal triglyceride-transfer protein in C3AT cells was not elevated. The accumulated [(3)H]TAG in C3AT microsomal lumen was mainly associated with lumenal IDL/LDL-like lipoproteins. Phenotypically, this [(3)H]TAG fractionation profiling resembled what was observed in cells treated with brefeldin A, which at low dose specifically blocked the second-step VLDL(1) maturation. Furthermore, lumenal [(35)S]Ala23Thr protein accumulated in IDL/LDL fractions and was absent in VLDL fractions in C3AT cells. These results suggest that the presence of Ala23Thr protein in lumenal IDL/LDL particles might prevent effective fusion between lipid droplets and VLDL precursors. Thus, the current study reveals an important structural element residing within the N-terminal region of apoC-III that governs the second step VLDL(1) maturation.
Authors:
Meenakshi Sundaram; Shumei Zhong; Maroun Bou Khalil; Hu Zhou; Zhenghui G Jiang; Yang Zhao; Jahangir Iqbal; M Mahmood Hussain; Daniel Figeys; Yuwei Wang; Zemin Yao
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-01-23
Journal Detail:
Title:  Journal of lipid research     Volume:  51     ISSN:  0022-2275     ISO Abbreviation:  J. Lipid Res.     Publication Date:  2010 Jun 
Date Detail:
Created Date:  2010-05-12     Completed Date:  2010-08-17     Revised Date:  2011-07-28    
Medline Journal Info:
Nlm Unique ID:  0376606     Medline TA:  J Lipid Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1524-34     Citation Subset:  IM    
Affiliation:
Department of Biochemistry, Ottawa Institute of Systems Biology, University of Ottawa, Canada.
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MeSH Terms
Descriptor/Qualifier:
Alanine / genetics
Apolipoproteins C / chemistry,  genetics*,  metabolism*
Brefeldin A / pharmacology
Carrier Proteins / metabolism
Cell Line
Gene Expression Regulation
Humans
Lipid Metabolism Disorders / genetics*
Lipoproteins, IDL / metabolism
Lipoproteins, LDL / metabolism
Lipoproteins, VLDL / metabolism
Microsomes / metabolism
Models, Molecular
Mutation, Missense*
Protein Binding / drug effects
Protein Structure, Secondary
Threonine / genetics
Triglycerides / metabolism*
Grant Support
ID/Acronym/Agency:
MT-15486//Canadian Institutes of Health Research
Chemical
Reg. No./Substance:
0/Apolipoproteins C; 0/Carrier Proteins; 0/Lipoproteins, IDL; 0/Lipoproteins, LDL; 0/Lipoproteins, VLDL; 0/Triglycerides; 0/microsomal triglyceride transfer protein; 20350-15-6/Brefeldin A; 56-41-7/Alanine; 72-19-5/Threonine
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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