title: Hepatic overexpression of idol increases circulating protein convertase subtilisin/kexin type 9 in mice and hamsters via dual mechanisms: sterol regulatory element-binding protein 2 and low-density lipoprotein receptor-dependent pathways.
abstract: OBJECTIVE
  Low-density lipoprotein receptor (LDLR) is degraded by inducible degrader of LDLR (Idol) and protein convertase subtilisin/kexin type 9 (PCSK9), thereby regulating circulating LDL levels. However, it remains unclear whether, and if so how, these LDLR degraders affect each other. We therefore investigated effects of liver-specific expression of Idol on LDL/PCSK9 metabolism in mice and hamsters.
  
  
  RESULTS
  Injection of adenoviral vector expressing Idol (Ad-Idol) induced a liver-specific reduction in LDLR expression which, in turn, increased very-low-density lipoprotein/LDL cholesterol levels in wild-type mice because of delayed LDL catabolism. Interestingly, hepatic Idol overexpression markedly increased plasma PCSK9 levels. In LDLR-deficient mice, plasma PCSK9 levels were already elevated at baseline and unchanged by Idol overexpression, which was comparable with the observation for Ad-Idol-injected wild-type mice, indicating that Idol-induced PCSK9 elevation depended on LDLR. In wild-type mice, but not in LDLR-deficient mice, Ad-Idol enhanced hepatic PCSK9 expression, with activation of sterol regulatory element-binding protein 2 and subsequently increased expression of its target genes. Supporting in vivo findings, Idol transactivated PCSK9/LDLR in sterol regulatory element-binding protein 2/LDLR-dependent manners in vitro. Furthermore, an in vivo kinetic study using (125)I-labeled PCSK9 revealed delayed clearance of circulating PCSK9, which could be another mechanism. Finally, to extend these findings into cholesteryl ester transfer protein-expressing animals, we repeated the above in vivo experiments in hamsters and obtained similar results.
  
  
  CONCLUSIONS
  A vicious cycle in LDLR degradation might be generated by PCSK9 induced by hepatic Idol overexpression via dual mechanisms: sterol regulatory element-binding protein 2/LDLR. Furthermore, these effects would be independent of cholesteryl ester transfer protein expression.
authors.affiliation: From the Division of Anti-aging and Vascular Medicine, Department of Internal Medicine (M.S., Y.T., M.A., H.U.-K., M.I., M.Y., S.T., E.Y., K.N., M.O., T.K., K.I.) and Department of Physiology (K.H.), National Defense Medical College, Tokorozawa, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Sasaki
authors.affiliation: From the Division of Anti-aging and Vascular Medicine, Department of Internal Medicine (M.S., Y.T., M.A., H.U.-K., M.I., M.Y., S.T., E.Y., K.N., M.O., T.K., K.I.) and Department of Physiology (K.H.), National Defense Medical College, Tokorozawa, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Terao
authors.affiliation: From the Division of Anti-aging and Vascular Medicine, Department of Internal Medicine (M.S., Y.T., M.A., H.U.-K., M.I., M.Y., S.T., E.Y., K.N., M.O., T.K., K.I.) and Department of Physiology (K.H.), National Defense Medical College, Tokorozawa, Japan. ayaori@ndmc.ac.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Ayaori
authors.affiliation: From the Division of Anti-aging and Vascular Medicine, Department of Internal Medicine (M.S., Y.T., M.A., H.U.-K., M.I., M.Y., S.T., E.Y., K.N., M.O., T.K., K.I.) and Department of Physiology (K.H.), National Defense Medical College, Tokorozawa, Japan.
authors.forename: Harumi
authors.initials: H
authors.lastname: Uto-Kondo
authors.affiliation: From the Division of Anti-aging and Vascular Medicine, Department of Internal Medicine (M.S., Y.T., M.A., H.U.-K., M.I., M.Y., S.T., E.Y., K.N., M.O., T.K., K.I.) and Department of Physiology (K.H.), National Defense Medical College, Tokorozawa, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Iizuka
authors.affiliation: From the Division of Anti-aging and Vascular Medicine, Department of Internal Medicine (M.S., Y.T., M.A., H.U.-K., M.I., M.Y., S.T., E.Y., K.N., M.O., T.K., K.I.) and Department of Physiology (K.H.), National Defense Medical College, Tokorozawa, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Yogo
authors.affiliation: From the Division of Anti-aging and Vascular Medicine, Department of Internal Medicine (M.S., Y.T., M.A., H.U.-K., M.I., M.Y., S.T., E.Y., K.N., M.O., T.K., K.I.) and Department of Physiology (K.H.), National Defense Medical College, Tokorozawa, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Hagisawa
authors.affiliation: From the Division of Anti-aging and Vascular Medicine, Department of Internal Medicine (M.S., Y.T., M.A., H.U.-K., M.I., M.Y., S.T., E.Y., K.N., M.O., T.K., K.I.) and Department of Physiology (K.H.), National Defense Medical College, Tokorozawa, Japan.
authors.forename: Shunichi
authors.initials: S
authors.lastname: Takiguchi
authors.affiliation: From the Division of Anti-aging and Vascular Medicine, Department of Internal Medicine (M.S., Y.T., M.A., H.U.-K., M.I., M.Y., S.T., E.Y., K.N., M.O., T.K., K.I.) and Department of Physiology (K.H.), National Defense Medical College, Tokorozawa, Japan.
authors.forename: Emi
authors.initials: E
authors.lastname: Yakushiji
authors.affiliation: From the Division of Anti-aging and Vascular Medicine, Department of Internal Medicine (M.S., Y.T., M.A., H.U.-K., M.I., M.Y., S.T., E.Y., K.N., M.O., T.K., K.I.) and Department of Physiology (K.H.), National Defense Medical College, Tokorozawa, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakaya
authors.affiliation: From the Division of Anti-aging and Vascular Medicine, Department of Internal Medicine (M.S., Y.T., M.A., H.U.-K., M.I., M.Y., S.T., E.Y., K.N., M.O., T.K., K.I.) and Department of Physiology (K.H.), National Defense Medical College, Tokorozawa, Japan.
authors.forename: Masatsune
authors.initials: M
authors.lastname: Ogura
authors.affiliation: From the Division of Anti-aging and Vascular Medicine, Department of Internal Medicine (M.S., Y.T., M.A., H.U.-K., M.I., M.Y., S.T., E.Y., K.N., M.O., T.K., K.I.) and Department of Physiology (K.H.), National Defense Medical College, Tokorozawa, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Komatsu
authors.affiliation: From the Division of Anti-aging and Vascular Medicine, Department of Internal Medicine (M.S., Y.T., M.A., H.U.-K., M.I., M.Y., S.T., E.Y., K.N., M.O., T.K., K.I.) and Department of Physiology (K.H.), National Defense Medical College, Tokorozawa, Japan.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Ikewaki
mesh_terms: D000818:Animals; D053480:Cholesterol Ester Transfer Proteins / Q000502:physiology; D006224:Cricetinae; D056945:Hep G2 Cells; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D000071518:Liver X Receptors; D008647:Mesocricetus; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors / Q000502:physiology; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000097:blood* / Q000502:physiology; D011973:Receptors, LDL / Q000502:physiology*; D012697:Serine Endopeptidases / Q000097:blood* / Q000502:physiology; D015398:Signal Transduction; D051782:Sterol Regulatory Element Binding Protein 2 / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*
chemical_list: D053480:Cholesterol Ester Transfer Proteins; D008077:Lipoproteins, LDL; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D011973:Receptors, LDL; D051782:Sterol Regulatory Element Binding Protein 2; C542022:Mylip protein, mouse; D044767:Ubiquitin-Protein Ligases; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
keywords: Idol protein, mouse; Pcsk9 protein, mouse; cholesterol ester transfer proteins; receptors, LDL