title: PCSK9 plays a significant role in cholesterol homeostasis and lipid transport in intestinal epithelial cells.
abstract: OBJECTIVE
  The proprotein convertase subtillisin/kexin type 9 (PCSK9) regulates cholesterol metabolism via degradation of low-density lipoprotein receptor (LDLr). Although PCSK9 is abundantly expressed in the intestine, limited data are available on its functions. The present study aims at determining whether PCSK9 plays important roles in cholesterol homeostasis and lipid transport in the gut.
  
  
  RESULTS
  Caco-2/15 cells were used allowing the exploration of the PCSK9 secretory route through the apical and basolateral compartments corresponding to intestinal lumen and serosal circulation, respectively. The output of PCSK9 occurred through the basolateral membrane, a site characterized by the location of LDLr. Co-immunoprecipitation studies indicated an association between PCSK9 and LDLr. Addition of purified recombinant wild type and D374Y gain-of function PCSK9 proteins to the basolateral medium was followed by a decrease in LDLr concomitantly with the accumulation of both forms of PCSK9. Furthermore, the latter caused a significant enhancement in cholesterol uptake also evidenced by a raised protein expression of cholesterol transporters NPC1L1 and CD36 without changes in SR-BI, ABCA1, and ABCG5/G8. Moreover, exogenous PCSK9 altered the activity of HMG-CoA reductase and acylcoenzyme A: cholesterol acyltransferase, and was able to enhance chylomicron secretion by positively modulating lipids and apolipoprotein B-48 biogenesis. Importantly, PCSK9 silencing led to opposite findings, which validate our data on the role of PCSK9 in lipid transport and metabolism. Moreover, PCSK9-mediated changes persisted despite LDLr knockdown.
  
  
  CONCLUSIONS
  These findings indicate that, in addition to its effect on LDLr, PCSK9 modulates cholesterol transport and metabolism, as well as production of apo B-containing lipoproteins in intestinal cells.
authors: Research Centre, CHU Ste-Justine, Université de Montréal, Québec, Canada. emile.levy@recherche-ste-Justine.qc.ca
authors: Emile
authors: E
authors: Levy
authors: Ali
authors: A
authors: Ben Djoudi Ouadda
authors: Schohraya
authors: S
authors: Spahis
authors: Alain Théophile
authors: AT
authors: Sane
authors: Carole
authors: C
authors: Garofalo
authors: Émilie
authors: É
authors: Grenier
authors: Lea
authors: L
authors: Emonnot
authors: Sabrina
authors: S
authors: Yara
authors: Patrick
authors: P
authors: Couture
authors: Jean-François
authors: JF
authors: Beaulieu
authors: Daniel
authors: D
authors: Ménard
authors: Nabil G
authors: NG
authors: Seidah
authors: Mounib
authors: M
authors: Elchebly
mesh_terms: D001692:Biological Transport; D018938:Caco-2 Cells; D002784:Cholesterol / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006706:Homeostasis; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D007422:Intestines / Q000166:cytology / Q000201:enzymology; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000378:metabolism; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000378:metabolism*; D011973:Receptors, LDL / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism*
chemical_list: D008074:Lipoproteins; D011973:Receptors, LDL; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases