title: Proprotein convertase subtilisin/kexin type 9 interacts with apolipoprotein B and prevents its intracellular degradation, irrespective of the low-density lipoprotein receptor.
abstract: OBJECTIVE
  proprotein convertase subtilisin/kexin type 9 (PCSK9) negatively regulates the low-density lipoprotein (LDL) receptor (LDLR) in hepatocytes and therefore plays an important role in controlling circulating levels of LDL-cholesterol. To date, the relationship between PCSK9 and metabolism of apolipoprotein B (apoB), the structural protein of LDL, has been controversial and remains to be clarified.
  
  
  RESULTS
  We assessed the impact of PCSK9 overexpression (≈400-fold above baseline) on apoB synthesis and secretion in 3 mouse models: wild-type C57BL/6 mice and LDLR-null mice (Ldlr(-/-) and Ldlr(-/-)Apobec1(-/-)). Irrespective of LDLR expression, mice transduced with the PCSK9 gene invariably exhibited increased levels of plasma cholesterol, triacylglycerol, and apoB. Consistent with these findings, the levels of very-low-density lipoprotein and LDL were also increased whereas high-density lipoprotein levels were unchanged. Importantly, we demonstrated that endogenous PCSK9 interacted with apoB in hepatocytes. The PCSK9/apoB interaction resulted in increased production of apoB, possibly through the inhibition of intracellular apoB degradation via the autophagosome/lysosome pathway.
  
  
  CONCLUSIONS
  We propose a new role for PCSK9 that involves shuttling between apoB and LDLR. The present study thus provides new insights into the action of PCSK9 in regulating apoB metabolism. Furthermore, our results indicate that targeting PCSK9 expression represents a new paradigm in therapeutic intervention against hyperlipidemia.
authors.affiliation: University of Texas Graduate School of Biomedical Sciences at Houston, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Sun
authors.forename: Amin
authors.initials: A
authors.lastname: Samarghandi
authors.forename: Ningyan
authors.initials: N
authors.lastname: Zhang
authors.forename: Zemin
authors.initials: Z
authors.lastname: Yao
authors.forename: Momiao
authors.initials: M
authors.lastname: Xiong
authors.forename: Ba-Bie
authors.initials: BB
authors.lastname: Teng
mesh_terms: D000818:Animals; D001055:Apolipoproteins B / Q000097:blood / Q000502:physiology*; D001343:Autophagy; D002784:Cholesterol / Q000097:blood; D056945:Hep G2 Cells; D006801:Humans; D008079:Lipoproteins, VLDL / Q000097:blood; D008247:Lysosomes / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000502:physiology*; D011973:Receptors, LDL / Q000502:physiology*; D012697:Serine Endopeptidases / Q000502:physiology*; D014280:Triglycerides / Q000097:blood
chemical_list: D001055:Apolipoproteins B; D008079:Lipoproteins, VLDL; D011973:Receptors, LDL; D014280:Triglycerides; D002784:Cholesterol; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases