PCSK7: A novel regulator of apolipoprotein B and a potential target against non-alcoholic fatty liver disease Journal Articles uri icon

  •  
  • Overview
  •  
  • Research
  •  
  • Identity
  •  
  • Additional Document Info
  •  
  • View All
  •  

abstract

  • BACKGROUND: Epidemiological evidence links the proprotein convertase subtilisin/kexin 7 (PCSK7) to triglyceride (TG) metabolism. We associated the known PCSK7 gain-of-function non-coding SNP rs236918 with higher levels of plasma apolipoprotein B (apoB) and the loss-of-function coding variant p.Pro777Leu (SNP rs201598301) with lower apoB and TG. Herein, we aimed to unravel the in vivo role of liver PCSK7. METHODS: We biochemically defined the functional role of PCSK7 in lipid metabolism using hepatic cell lines and Pcsk7-/- mice. Our findings were validated following subcutaneous administration of hepatocyte-targeted N-acetylgalactosamine (GalNAc)-antisense oligonucleotides (ASOs) against Pcsk7. RESULTS: Independent of its proteolytic activity, membrane-bound PCSK7 binds apoB100 in the endoplasmic reticulum and enhances its secretion. Mechanistically, the loss of PCSK7/Pcsk7 leads to apoB100 degradation, triggering an unfolded protein response, autophagy, and β-oxidation, eventually reducing lipid accumulation in hepatocytes. Non-alcoholic fatty liver disease (NAFLD) was induced by a 12-week high fat/fructose/cholesterol diet in wild type (WT) and Pcsk7-/- mice that were then allowed to recover on a 4-week control diet. Pcsk7-/- mice recovered more effectively than WT mice from all NAFLD-related liver phenotypes. Finally, subcutaneous administration of GalNAc-ASOs targeting hepatic Pcsk7 to WT mice validated the above results. CONCLUSIONS: Our data reveal hepatic PCSK7 as one of the major regulators of apoB, and its absence reduces apoB secretion from hepatocytes favoring its ubiquitination and degradation by the proteasome. This results in a cascade of events, eventually reducing hepatic lipid accumulation, thus supporting the notion of silencing PCSK7 mRNA in hepatocytes for targeting NAFLD.

authors

  • Sachan, Vatsal
  • Le Dévéhat, Maïlys
  • Roubtsova, Anna
  • Essalmani, Rachid
  • Laurendeau, Jean-Francois
  • Garçon, Damien
  • Susan-Resiga, Delia
  • Duval, Stéphanie
  • Mikaeeli, Sahar
  • Hamelin, Josée
  • Evagelidis, Alexandra
  • Chong, Michael
  • Pare, Guillaume
  • Chernetsova, Elizabeta
  • Gao, Zu-Hua
  • Robillard, Isabelle
  • Ruiz, Matthieu
  • Trinh, Vincent Quoc-Huy
  • Estall, Jennifer L
  • Faraj, May
  • Austin, Richard C
  • Sauvageau, Martin
  • Prat, Annik
  • Kiss, Robert S
  • Seidah, Nabil G

publication date

  • January 2024