Protein phosphatase 2A (PP2A) regulates low density lipoprotein uptake through regulating sterol response element-binding protein-2 (SREBP-2) DNA binding.
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.
From the Oncoveda Cancer Institute and.
Lyndi M
LM
Rice
the Institute of Metabolic Disorders, Genesis Biotechnology Group, Hamilton, New Jersey 08691 and.
Melissa
M
Donigan
the Institute of Metabolic Disorders, Genesis Biotechnology Group, Hamilton, New Jersey 08691 and.
Muhua
M
Yang
the Institute of Metabolic Disorders, Genesis Biotechnology Group, Hamilton, New Jersey 08691 and.
Weidong
W
Liu
the Institute of Metabolic Disorders, Genesis Biotechnology Group, Hamilton, New Jersey 08691 and.
Devanshi
D
Pandya
the Institute of Metabolic Disorders, Genesis Biotechnology Group, Hamilton, New Jersey 08691 and.
Biny K
BK
Joseph
From the Oncoveda Cancer Institute and.
Valerie
V
Sodi
the Department of Molecular Biology and Biochemistry, Drexel University College of Medicine, Philadelphia, Pennsylvania 19129.
Tricia L
TL
Gearhart
the Institute of Metabolic Disorders, Genesis Biotechnology Group, Hamilton, New Jersey 08691 and.
Jenny
J
Yip
the Department of Molecular Biology and Biochemistry, Drexel University College of Medicine, Philadelphia, Pennsylvania 19129.
Michael
M
Bouchard
the Institute of Metabolic Disorders, Genesis Biotechnology Group, Hamilton, New Jersey 08691 and jnickels@venenumbiodesign.com.
Joseph T
JT
Nickels
D021581:Active Transport, Cell Nucleus; D008078:Cholesterol, LDL / Q000172:deficiency / Q000378:metabolism*; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D011485:Protein Binding; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D020218:Response Elements; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism*
D008078:Cholesterol, LDL; C573412:LDLR protein, human; D011973:Receptors, LDL; C497390:SREBF2 protein, human; D051782:Sterol Regulatory Element Binding Protein 2; C517189:PPP2CA protein, human; D054648:Protein Phosphatase 2
Cholesterol; DNA; Lipid; Lipoprotein; Low Density Lipoprotein (LDL); Metabolism; SREBP; Transcription