Functional analysis of the missense APOC3 mutation Ala23Thr associated with human hypotriglyceridemia

2010/01/25 by Meenakshi Sundaram, Shumei Zhong, Maroun Bou Khalil +8 · 5 citations
Medicine · Biochemistry, Genetics and Molecular Biology · #Lipid metabolism and disorders #Lipid metabolism and biosynthesis #Diabetes, Cardiovascular Risks, and Lipoproteins #Missense mutation #Mutation #Genetics #Biology #Gene

paper · pdf · doi:10.1194/jlr.m005108

openalex publication_date 2010/01/25 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/28

Abstract

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.

Citations

• Apolipoprotein C-III(Lys58----Glu). Identification of an apolipoprotein C-III variant in a family with hyperalphalipoproteinemia.
• Expression of apolipoprotein C-III in McA-RH7777 cells enhances VLDL assembly and secretion under lipid-rich conditions
• Systematic risk behavior of financially distressed firms

Cited by

• A human APOC3 missense variant and monoclonal antibody accelerate apoC-III clearance and lower triglyceride-rich lipoprotein levels
• Missense Mutation in APOC3 within the C-terminal Lipid Binding Domain of Human ApoC-III Results in Impaired Assembly and Secretion of Triacylglycerol-rich Very Low Density Lipoproteins
• Recent advances in physiological lipoprotein metabolism
• FoxO6-mediated ApoC3 upregulation promotes hepatic steatosis and hyperlipidemia in aged rats fed a high-fat diet
• Apolipoprotein C-III [wikipedia]

Related

• Missense Mutation in APOC3 within the C-terminal Lipid Binding Domain of Human ApoC-III Results in Impaired Assembly and Secretion of Triacylglycerol-rich Very Low Density Lipoproteins
• ABCA1 Promotes the de Novo Biogenesis of Apolipoprotein CIII-Containing HDL Particles in Vivo and Modulates the Severity of Apolipoprotein CIII-Induced Hypertriglyceridemia
• Biosynthesis and Metabolism of ApoB-Containing Lipoproteins
• Complexities of plasma apolipoprotein C-III metabolism
• The crucial roles of apolipoproteins E and C-III in apoB lipoprotein metabolism in normolipidemia and hypertriglyceridemia