Protein phosphatase 2A (PP2A) regulates low density lipoprotein uptake through regulating sterol response element-binding protein-2 (SREBP-2) DNA binding

J Biol Chem. 2014 Jun 13;289(24):17268-79. doi: 10.1074/jbc.M114.570390. Epub 2014 Apr 26.


LDL-cholesterol (LDL-C) uptake by Ldlr is regulated at the transcriptional level by the cleavage-dependent activation of membrane-associated sterol response element-binding protein (SREBP-2). Activated SREBP-2 translocates to the nucleus, where it binds to an LDLR promoter sterol response element (SRE), increasing LDLR gene expression and LDL-C uptake. SREBP-2 cleavage and translocation steps are well established. Several SREBP-2 phosphorylation sites have been mapped and functionally characterized. The phosphatases dephosphorylating these sites remain elusive. The phosphatase(s) regulating SREBP-2 represents a novel pharmacological target for treating hypercholesterolemia. Here we show that protein phosphatase 2A (PP2A) promotes SREBP-2 LDLR promoter binding in response to cholesterol depletion. No binding to an LDLR SRE was observed in the presence of the HMG-CoA reductase inhibitor, lovastatin, when PP2A activity was inhibited by okadaic acid or depleted by siRNA methods. SREBP-2 cleavage and nuclear translocation were not affected by loss of PP2A. PP2A activity was required for SREBP-2 DNA binding. In response to cholesterol depletion, PP2A directly interacted with SREBP-2 and altered its phosphorylation state, causing an increase in SREBP-2 binding to an LDLR SRE site. Increased binding resulted in induced LDLR gene expression and increased LDL uptake. We conclude that PP2A activity regulates cholesterol homeostasis and LDL-C uptake.

Keywords: Cholesterol; DNA; Lipid; Lipoprotein; Low Density Lipoprotein (LDL); Metabolism; SREBP; Transcription.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Cholesterol, LDL / deficiency
  • Cholesterol, LDL / metabolism*
  • HEK293 Cells
  • Hep G2 Cells
  • Humans
  • Protein Binding
  • Protein Phosphatase 2 / genetics
  • Protein Phosphatase 2 / metabolism*
  • Receptors, LDL / genetics
  • Receptors, LDL / metabolism
  • Response Elements*
  • Sterol Regulatory Element Binding Protein 2 / metabolism*


  • Cholesterol, LDL
  • LDLR protein, human
  • Receptors, LDL
  • SREBF2 protein, human
  • Sterol Regulatory Element Binding Protein 2
  • PPP2CA protein, human
  • Protein Phosphatase 2