PubMed:36865344 JSONTXT

{"project":"PubTator4TogoVar","denotations":[{"id":"36865344_0","span":{"begin":981,"end":986},"obj":"ProteinMutation"},{"id":"36865344_1","span":{"begin":886,"end":891},"obj":"ProteinMutation"},{"id":"36865344_2","span":{"begin":1380,"end":1385},"obj":"ProteinMutation"},{"id":"36865344_3","span":{"begin":1080,"end":1085},"obj":"ProteinMutation"}],"attributes":[{"id":"36865344_0_ProteinMutation","pred":"proteinmutation","subj":"36865344_0","obj":"rs149808404"},{"id":"36865344_1_ProteinMutation","pred":"proteinmutation","subj":"36865344_1","obj":"rs149808404"},{"id":"36865344_2_ProteinMutation","pred":"proteinmutation","subj":"36865344_2","obj":"rs149808404"},{"id":"36865344_3_ProteinMutation","pred":"proteinmutation","subj":"36865344_3","obj":"rs149808404"}],"text":"Comparison of the structure-function properties of wild-type human apoA-V and a C-terminal truncation associated with elevated plasma triglycerides.\nBACKGROUND: 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.\nMETHODS: 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.\nRESULTS: 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.\nCONCLUSIONS: 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."}