Dataset Information

Comparison of the structure-function properties of wild-type human apoA-V and a C-terminal truncation associated with elevated plasma triglycerides.

ABSTRACT:

Background

Plasma triglycerides (TGs) are causally associated with coronary artery disease and acute pancreatitis. Apolipoprotein A-V (apoA-V, gene APOA5) is a liver-secreted protein that is carried on triglyceride-rich lipoproteins and promotes the enzymatic activity of lipoprotein lipase (LPL), thereby reducing TG levels. Little is known about apoA-V structure-function; naturally occurring human APOA5 variants can provide novel insights.

Methods

We used hydrogen-deuterium exchange mass spectrometry to determine the secondary structure of human apoA-V in lipid-free and lipid-associated conditions and identified a C-terminal hydrophobic face. Then, we used genomic data in the Penn Medicine Biobank to identify a rare variant, Q252X, predicted to specifically eliminate this region. We interrogated the function of apoA-V Q252X using recombinant protein in vitro and in vivo in apoa5 knockout mice.

Results

Human apoA-V Q252X carriers exhibited elevated plasma TG levels consistent with loss of function. Apoa5 knockout mice injected with AAV vectors expressing wildtype and variant APOA5-AAV recapitulated this phenotype. Part of the loss of function is due to reduced mRNA expression. Functionally, recombinant apoA-V Q252X was more readily soluble in aqueous solutions and more exchangeable with lipoproteins than WT apoA-V. Despite lacking the C-terminal hydrophobic region (a putative lipid binding domain) this protein also decreased plasma TG in vivo.

Conclusions

Deletion of apoA-V's C-terminus leads to reduced apoA-V bioavailability in vivo and higher TG levels. However, the C-terminus is not required for lipoprotein binding or enhancement of intravascular lipolytic activity. WT apoA-V is highly prone to aggregation, and this property is markedly reduced in recombinant apoA-V lacking the C-terminus.

SUBMITTER: Stankov S

PROVIDER: S-EPMC9980232 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Publications

Comparison of the structure-function properties of wild-type human apoA-V and a C-terminal truncation associated with elevated plasma triglycerides.

Stankov Sylvia S Vitali Cecilia C Park Joseph J Nguyen David D Mayne Leland L Englander S Walter SW Levin Michael G MG Vujkovic Marijana M Hand Nicholas J NJ Phillips Michael C MC Rader Daniel J DJ

medRxiv : the preprint server for health sciences 20230223

<h4>Background</h4>Plasma triglycerides (TGs) are causally associated with coronary artery disease and acute pancreatitis. Apolipoprotein A-V (apoA-V, gene <i>APOA5</i>) is a liver-secreted protein that is carried on triglyceride-rich lipoproteins and promotes the enzymatic activity of lipoprotein lipase (LPL), thereby reducing TG levels. Little is known about apoA-V structure-function; naturally occurring human <i>APOA5</i> variants can provide novel insights.<h4>Methods</h4>We used hydrogen-de ...[more]

PMID: 36865344

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Dataset Information

Comparison of the structure-function properties of wild-type human apoA-V and a C-terminal truncation associated with elevated plasma triglycerides.

Background

Methods

Results

Conclusions

Publications

Comparison of the structure-function properties of wild-type human apoA-V and a C-terminal truncation associated with elevated plasma triglycerides.

Similar Datasets

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