APP, APLP2 and LRP1 interact with PCSK9 but are not required for PCSK9-mediated degradation of the LDLR in vivo

Biochim Biophys Acta Mol Cell Biol Lipids. 2017 Sep;1862(9):883-889. doi: 10.1016/j.bbalip.2017.05.002. Epub 2017 May 9.

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that post-transcriptionally regulates the levels of hepatic low-density lipoprotein receptors (LDLRs). PCSK9 binds to the extracellular domain of the LDLR, and the PCSK9-LDLR complex is internalized through canonical clathrin-dependent endocytosis and then delivered to lysosomes for degradation. The mechanism by which PCSK9 blocks recycling of the LDLR has not been fully defined. Previous reports showed that amyloid precursor-like protein 2 (APLP2) interacts with PCSK9, but its role in PCSK9-mediated LDLR degradation remains controversial. Here we found that amyloid precursor protein (APP), APLP2 and LDL receptor-related protein 1 (LRP1) interact with PCSK9. To test whether any of these proteins are required for PCSK9-mediated LDLR degradation, we examined the effects of disrupting these proteins in mice. Infusion of PCSK9 into App-/-, Aplp2-/-, Aplp2-depleted App-/-, or liver-specific Lrp1-/- mice resulted in similar reductions in the levels of hepatic LDLR as seen in wild-type (WT) mice. Infusion of PCSK9 into WT mice also had no effect on the levels of hepatic APP, APLP2 or LRP1. Thus, APP, APLP2 and LRP1 are not required for PCSK9-mediated LDLR degradation and are not regulated by PCSK9 in vivo.

Keywords: Cholesterol; Crosslinking; Degradation; Endocytosis; Endosome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Cell Line, Tumor
  • Endocytosis / physiology
  • Hepatocytes / metabolism
  • Hepatocytes / physiology
  • Humans
  • Lipoproteins, LDL / metabolism
  • Liver / metabolism
  • Liver / physiology
  • Low Density Lipoprotein Receptor-Related Protein-1 / metabolism*
  • Lysosomes / metabolism
  • Lysosomes / physiology
  • Mice
  • Proprotein Convertase 9 / metabolism*
  • Receptors, LDL / metabolism*

Substances

  • Amyloid beta-Protein Precursor
  • Lipoproteins, LDL
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Receptors, LDL
  • Proprotein Convertase 9