Proprotein convertase 7 (PCSK7) reduces apoA-V levels

Area of Science:

• Lipid metabolism and cardiovascular disease genetics.
• Molecular mechanisms of protein regulation.
• Gene-environment interactions in metabolic disorders.

Background:

• The PCSK7 gene, encoding proprotein convertase subtilisin-kexin type-7 (PC7), is located near genes regulating lipoprotein metabolism.
• Genetic variations in PCSK7 are associated with plasma triglyceride (TG) levels.
• A specific PC7 variant (R504H) is linked to significantly reduced TG.

Purpose of the Study:

• To investigate the hypothesis that PC7 regulates apolipoprotein A-V (apoA-V) levels and activity.
• To elucidate the molecular mechanism by which PC7 influences TG metabolism.
• To explore the role of PC7 in vivo in the context of a high-fat diet.

Main Methods:

• Studies in human hepatic (HuH7) cell lines to assess PC7-apoA-V interaction and degradation.
• In vitro experiments using PC7 mutants and phosphomimetic variants.
• Analysis of Pcsk7 knockout mice fed a high-fat diet.

Main Results:

• Wild-type PC7 enhances the lysosomal degradation of apoA-V in hepatic cells.
• PC7-induced apoA-V degradation is an ER-lysosomal communication process.
• PC7 phosphorylation at Ser505, influenced by the R504H variant, reduces apoA-V degradation.
• Pcsk7 knockout mice exhibit increased apoA-V levels and adipocyte lipoprotein lipase (LpL) activity on a high-fat diet.

Conclusions:

• Liver PC7 promotes apoA-V degradation, thereby lowering plasma triglyceride levels.
• PC7-mediated apoA-V degradation involves ER-lysosomal transport and is modulated by PC7 phosphorylation.
• These findings establish an in vivo link between PC7, apoA-V, and TG storage in adipocytes, highlighting PC7 as a potential therapeutic target for hypertriglyceridemia.