Endoplasmic Reticulum Stress and Ca2+ Depletion Differentially Modulate the Sterol Regulatory Protein PCSK9 to Control Lipid Metabolism

J Biol Chem. 2017 Jan 27;292(4):1510-1523. doi: 10.1074/jbc.M116.744235. Epub 2016 Dec 1.


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.

Keywords: ER calcium; SREBP2; cholesterol; endoplasmic reticulum stress (ER stress); hepatocyte; hepatocytes; low density lipoprotein (LDL); proprotein convertase subtilisin/kexin type 9 (PCSK9).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Endoplasmic Reticulum Stress*
  • Gene Expression Regulation, Enzymologic*
  • Hep G2 Cells
  • Hepatocytes / metabolism*
  • Humans
  • Lipid Metabolism*
  • Male
  • Mice
  • Proprotein Convertase 9 / biosynthesis*
  • Proprotein Convertase 9 / genetics
  • Proteolysis
  • Receptors, LDL / genetics
  • Sterol Regulatory Element Binding Protein 2 / genetics
  • Sterol Regulatory Element Binding Protein 2 / metabolism


  • LDLR protein, human
  • Receptors, LDL
  • SREBF2 protein, human
  • Srebf2 protein, mouse
  • Sterol Regulatory Element Binding Protein 2
  • PCSK9 protein, human
  • Pcsk9 protein, mouse
  • Proprotein Convertase 9
  • Calcium