title: Endoplasmic Reticulum Stress and Ca2+ Depletion Differentially Modulate the Sterol Regulatory Protein PCSK9 to Control Lipid Metabolism.
abstract: Accumulating evidence implicates endoplasmic reticulum (ER) stress as a mediator of impaired lipid metabolism, thereby contributing to fatty liver disease and atherosclerosis. Previous studies demonstrated that ER stress can activate the sterol regulatory element-binding protein-2 (SREBP2), an ER-localized transcription factor that directly up-regulates sterol regulatory genes, including PCSK9 Given that PCSK9 contributes to atherosclerosis by targeting low density lipoprotein (LDL) receptor (LDLR) degradation, this study investigates a novel mechanism by which ER stress plays a role in lipid metabolism by examining its ability to modulate PCSK9 expression. Herein, we demonstrate the existence of two independent effects of ER stress on PCSK9 expression and secretion. In cultured HuH7 and HepG2 cells, agents or conditions that cause ER Ca2+depletion, including thapsigargin, induced SREBP2-dependent up-regulation of PCSK9 expression. In contrast, a significant reduction in the secreted form of PCSK9 protein was observed in the media from both thapsigargin- and tunicamycin (TM)-treated HuH7 cells, mouse primary hepatocytes, and in the plasma of TM-treated C57BL/6 mice. Furthermore, TM significantly increased hepatic LDLR expression and reduced plasma LDL concentrations in mice. Based on these findings, we propose a model in which ER Ca2+depletion promotes the activation of SREBP2 and subsequent transcription of PCSK9. However, conditions that cause ER stress regardless of their ability to dysregulate ER Ca2+inhibit PCSK9 secretion, thereby reducing PCSK9-mediated LDLR degradation and promoting LDLR-dependent hepatic cholesterol uptake. Taken together, our studies provide evidence that the retention of PCSK9 in the ER may serve as a potential strategy for lowering LDL cholesterol levels.
authors.affiliation: From the Department of Medicine, Division of Nephrology, McMaster University and St. Joseph's Hamilton Healthcare and Hamilton Centre for Kidney Research, Hamilton, Ontario L8N 4A6.
authors.forename: Paul
authors.initials: P
authors.lastname: Lebeau
authors.affiliation: From the Department of Medicine, Division of Nephrology, McMaster University and St. Joseph's Hamilton Healthcare and Hamilton Centre for Kidney Research, Hamilton, Ontario L8N 4A6.
authors.forename: Ali
authors.initials: A
authors.lastname: Al-Hashimi
authors.affiliation: From the Department of Medicine, Division of Nephrology, McMaster University and St. Joseph's Hamilton Healthcare and Hamilton Centre for Kidney Research, Hamilton, Ontario L8N 4A6.
authors.forename: Sudesh
authors.initials: S
authors.lastname: Sood
authors.affiliation: From the Department of Medicine, Division of Nephrology, McMaster University and St. Joseph's Hamilton Healthcare and Hamilton Centre for Kidney Research, Hamilton, Ontario L8N 4A6.
authors.forename: Šárka
authors.initials: Š
authors.lastname: Lhoták
authors.affiliation: the Thrombosis and Atherosclerosis Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario L8L 2X2.|the Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8S 4L8.
authors.forename: Pei
authors.initials: P
authors.lastname: Yu
authors.affiliation: From the Department of Medicine, Division of Nephrology, McMaster University and St. Joseph's Hamilton Healthcare and Hamilton Centre for Kidney Research, Hamilton, Ontario L8N 4A6.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Gyulay
authors.affiliation: the Population Health Research Institute and the Departments of Medicine, Epidemiology and Pathology, McMaster University, Hamilton, Ontario L8L 2X2.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Paré
authors.affiliation: the Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta T2N 2T9, and.
authors.forename: S R Wayne
authors.initials: SR
authors.lastname: Chen
authors.affiliation: the Thrombosis and Atherosclerosis Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario L8L 2X2.|the Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8S 4L8.
authors.forename: Bernardo
authors.initials: B
authors.lastname: Trigatti
authors.affiliation: the Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, affiliated with the University of Montreal, Montreal, Quebec H2W 1R7, Canada.
authors.forename: Annik
authors.initials: A
authors.lastname: Prat
authors.affiliation: the Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, affiliated with the University of Montreal, Montreal, Quebec H2W 1R7, Canada.
authors.forename: Nabil G
authors.initials: NG
authors.lastname: Seidah
authors.affiliation: From the Department of Medicine, Division of Nephrology, McMaster University and St. Joseph's Hamilton Healthcare and Hamilton Centre for Kidney Research, Hamilton, Ontario L8N 4A6, austinr@taari.ca.|the Thrombosis and Atherosclerosis Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario L8L 2X2.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Austin
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D015971:Gene Expression Regulation, Enzymologic; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D000071449:Proprotein Convertase 9 / Q000096:biosynthesis* / Q000235:genetics; D059748:Proteolysis; D011973:Receptors, LDL / Q000235:genetics; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000378:metabolism
chemical_list: C573412:LDLR protein, human; D011973:Receptors, LDL; C497390:SREBF2 protein, human; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; C472125:PCSK9 protein, human; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9; D002118:Calcium
keywords: ER calcium; SREBP2; cholesterol; endoplasmic reticulum stress (ER stress); hepatocyte; hepatocytes; low density lipoprotein (LDL); proprotein convertase subtilisin/kexin type 9 (PCSK9)