Identification of a Chrysanthemic Ester as an Apolipoprotein E Inducer in Astrocytes.
The apolipoprotein E (APOE) gene is the most highly associated susceptibility locus for late onset Alzheimer's Disease (AD), and augmenting the beneficial physiological functions of apoE is a proposed therapeutic strategy. In a high throughput phenotypic screen for small molecules that enhance apoE secretion from human CCF-STTG1 astrocytoma cells, we show the chrysanthemic ester 82879 robustly increases expressed apoE up to 9.4-fold and secreted apoE up to 6-fold and is associated with increased total cholesterol in conditioned media. Compound 82879 is unique as structural analogues, including pyrethroid esters, show no effect on apoE expression or secretion. 82879 also stimulates liver x receptor (LXR) target genes including ATP binding cassette A1 (ABCA1), LXRα and inducible degrader of low density lipoprotein receptor (IDOL) at both mRNA and protein levels. In particular, the lipid transporter ABCA1 was increased by up to 10.6-fold upon 82879 treatment. The findings from CCF-STTG1 cells were confirmed in primary human astrocytes from three donors, where increased apoE and ABCA1 was observed along with elevated secretion of high-density lipoprotein (HDL)-like apoE particles. Nuclear receptor transactivation assays revealed modest direct LXR agonism by compound 82879, yet 10 μM of 82879 significantly upregulated apoE mRNA in mouse embryonic fibroblasts (MEFs) depleted of both LXRα and LXRβ, demonstrating that 82879 can also induce apoE expression independent of LXR transactivation. By contrast, deletion of LXRs in MEFs completely blocked mRNA changes in ABCA1 even at 10 μM of 82879, indicating the ability of 82879 to stimulate ABCA1 expression is entirely dependent on LXR transactivation. Taken together, compound 82879 is a novel chrysanthemic ester capable of modulating apoE secretion as well as apoE-associated lipid metabolic pathways in astrocytes, which is structurally and mechanistically distinct from known LXR agonists.
Department of Pathology and Laboratory Medicine, University of British Columbia, Djavad Mowafaghian Centre for Brain Health, Vancouver, British Columbia, Canada.
Jianjia
J
Fan
Department of Pathology and Laboratory Medicine, University of British Columbia, Djavad Mowafaghian Centre for Brain Health, Vancouver, British Columbia, Canada.
Shahab
S
Zareyan
Department of Pathology and Laboratory Medicine, University of British Columbia, Djavad Mowafaghian Centre for Brain Health, Vancouver, British Columbia, Canada.
Wenchen
W
Zhao
Centre for Drug Research and Development, Vancouver, British Columbia, Canada.
Yoko
Y
Shimizu
Centre for Drug Research and Development, Vancouver, British Columbia, Canada.
Tom A
TA
Pfeifer
Faculty of Land and Food Systems, University of British Columbia, Vancouver, British Columbia, Canada.
Jun-Hyung
JH
Tak
Faculty of Land and Food Systems, University of British Columbia, Vancouver, British Columbia, Canada.
Murray B
MB
Isman
TC Scientific Inc., Edmonton, Alberta, Canada.
Bernard
B
Van den Hoven
AstraZeneca, Cambridge, Massachusetts, United States of America.
Mark E
ME
Duggan
AstraZeneca, Cambridge, Massachusetts, United States of America.
Michael W
MW
Wood
Department of Pathology and Laboratory Medicine, University of British Columbia, Djavad Mowafaghian Centre for Brain Health, Vancouver, British Columbia, Canada.
Cheryl L
CL
Wellington
Department of Pathology and Laboratory Medicine, University of British Columbia, Djavad Mowafaghian Centre for Brain Health, Vancouver, British Columbia, Canada.
Iva
http://orcid.org/0000-0001-9093-113X
I
Kulic
D064286:ATP Binding Cassette Transporter 1 / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D045744:Cell Line, Tumor; D004952:Esters; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D057166:High-Throughput Screening Assays; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D000071518:Liver X Receptors / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture; D011722:Pyrethrins / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; C000612345:ApoE protein, human; D001057:Apolipoproteins E; D004952:Esters; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D011722:Pyrethrins; D012333:RNA, Messenger; D011973:Receptors, LDL; C007051:chrysanthemic acid