title: Human PCSK9 promotes hepatic lipogenesis and atherosclerosis development via apoE- and LDLR-mediated mechanisms.
abstract: OBJECTIVE
  Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of hepatic low-density lipoprotein (LDL) receptors (LDLR), thereby, decreasing hepatocyte LDL-cholesterol (LDL-C) uptake. However, it is unknown whether PCSK9 has effects on atherogenesis that are independent of lipid changes. The present study investigated the effect of human (h) PCSK9 on plasma lipids, hepatic lipogenesis, and atherosclerotic lesion size and composition in transgenic mice expressing hPCSK9 (hPCSK9tg) on wild-type (WT), LDLR⁻/⁻, or apoE⁻/⁻ background.
  
  
  RESULTS
  hPCSK9 expression significantly increased plasma cholesterol (+91%), triglycerides (+18%), and apoB (+57%) levels only in WT mice. The increase in plasma lipids was a consequence of both decreased hepatic LDLR and increased hepatic lipid production, mediated transcriptionally and post-transcriptionally by PCSK9 and dependent on both LDLR and apoE. Despite the lack of changes in plasma lipids in mice expressing hPCSK9 and lacking LDLR (the main target for PCSK9) or apoE (a canonical ligand for the LDLR), hPCSK9 expression increased aortic lesion size in the absence of apoE (268 655 ± 97 972 µm² in hPCSK9tg/apoE⁻/⁻ vs. 189 423 ± 65 700 µm(2) in apoE⁻/⁻) but not in the absence of LDLR. Additionally, hPCSK9 accumulated in the atheroma and increased lesion Ly6C(hi) monocytes (by 21%) in apoE⁻/⁻ mice, but not in LDLR⁻/⁻ mice.
  
  
  CONCLUSIONS
  PCSK9 increases hepatic lipid and lipoprotein production via apoE- and LDLR-dependent mechanisms. However, hPCSK9 also accumulate in the artery wall and directly affects atherosclerosis lesion size and composition independently of such plasma lipid and lipoprotein changes. These effects of hPCSK9 are dependent on LDLR but are independent of apoE.
authors.affiliation: Knight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health and Science University, Portland, OR, USA fazio@ohsu.edu tavori@ohsu.edu.
authors.forename: Hagai
authors.initials: H
authors.lastname: Tavori
authors.affiliation: Knight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health and Science University, Portland, OR, USA.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Giunzioni
authors.affiliation: Knight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health and Science University, Portland, OR, USA.
authors.forename: Irene M
authors.initials: IM
authors.lastname: Predazzi
authors.affiliation: Knight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health and Science University, Portland, OR, USA.
authors.forename: Deanna
authors.initials: D
authors.lastname: Plubell
authors.affiliation: Knight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health and Science University, Portland, OR, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Shivinsky
authors.affiliation: Knight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health and Science University, Portland, OR, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Miles
authors.affiliation: Rinat Laboratory, Pfizer Inc., South San Francisco, CA, USA.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Devay
authors.affiliation: Rinat Laboratory, Pfizer Inc., South San Francisco, CA, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Liang
authors.affiliation: Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada Dalhousie Medicine New Brunswick University, Saint John, New Brunswick, Canada.
authors.forename: Shirya
authors.initials: S
authors.lastname: Rashid
authors.affiliation: Division of Cardiovascular Medicine, Atherosclerosis Research Unit, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: MacRae F
authors.initials: MF
authors.lastname: Linton
authors.affiliation: Knight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health and Science University, Portland, OR, USA fazio@ohsu.edu tavori@ohsu.edu.
authors.forename: Sergio
authors.initials: S
authors.lastname: Fazio
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000378:metabolism*; D008078:Cholesterol, LDL / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D050155:Lipogenesis / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071449:Proprotein Convertase 9 / Q000235:genetics / Q000378:metabolism*; D011973:Receptors, LDL / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D008078:Cholesterol, LDL; D011973:Receptors, LDL; D014280:Triglycerides; C472125:PCSK9 protein, human; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9
keywords: Atherosclerosis; Hepatocytes; Lipoproteins; Murine models; PCSK9