Lipids

, Volume 44, Issue 8, pp 673–683

Docosahexaenoic Acid Activates Some SREBP-2 Targets Independent of Cholesterol and ER Stress in SW620 Colon Cancer Cells

  • Gro Leite Størvold
  • Karianne Giller Fleten
  • Cathrine Goberg Olsen
  • Turid Follestad
  • Hans Einar Krokan
  • Svanhild Arentz Schønberg
Original Article

Abstract

The SREBP-2 transcription factor is mainly activated by low cellular cholesterol levels. However, other factors may also cause SREBP-2 activation. We have previously demonstrated activation of SREBP-2 by the polyunsaturated fatty acid docosahexaenoic acid (DHA) in SW620 colon cancer cells. Despite activation of SREBP-2, only a few target genes were induced and cholesterol biosynthesis was reduced. In the present study, gene expression analysis at early time points verified the previously observed SREBP-2 target gene expression pattern. Activation of SREBP-2 using siRNAs targeting Niemann Pick C1 protein (NPC1) led to increased expression of all SREBP target genes examined, indicating that activation of some SREBP-2 target genes is inhibited during DHA-treatment. Cholesterol supplementation during DHA treatment did not abolish SREBP-2 activation. We also demonstrate that activation of SREBP-2 is independent of ER stress and eIF2α phosphorylation, which we have previously observed in DHA-treated cells. Thapsigargin-induced ER stress repressed expression of SREBP-2 target genes, but with a different pattern than observed in DHA-treated cells. Moreover, oleic acid (OA) treatment, which does not induce ER stress in SW620 cells, led to activation of SREBP-2 and induced a target gene expression pattern similar to that of DHA-treated cells. These results indicate that DHA and OA may activate SREBP-2 and inhibit activation of SREBP-2 target genes through a mechanism independent of cholesterol level and ER stress.

Keywords

SREBP-2 Cholesterol biosynthesis ER stress Transcriptional regulation eIF2α 

Abbreviations

ATF6

Activating transcription factor 6

DHA

Docosahexaenoic acid

DnaJA4

DnaJ (Hsp 40) homolog-subfamily A-member 4

ER

Endoplasmic reticulum

eIF2α

Eukaryote translation initiation factor 2 alpha

FA

Fatty acid

FDFT

Farnesyl diphosphate farnesyltransferase

HMGCR

3-Hydroxy-3-methylglutaryl-coenzyme A reductase

IDI

Isopentenyl-diphosphate delta isomerase

Insig

Insulin induced gene

LDLR

Low density lipoprotein receptor

NPC1

Niemann Pick C1

OA

Oleic acid

PUFA

Polyunsaturated fatty acid

SCAP

SREBP cleavage activating protein

siRNA

Small interfering RNA

SRE

Sterol regulatory element

SREBP

SRE binding protein

mSREBP

Mature SREBP

SQS

Squalene synthetase

Tg

Thapsigargin

UFA

Unsaturated fatty acid

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Copyright information

© AOCS 2009

Authors and Affiliations

  • Gro Leite Størvold
    • 1
  • Karianne Giller Fleten
    • 1
  • Cathrine Goberg Olsen
    • 1
  • Turid Follestad
    • 2
  • Hans Einar Krokan
    • 3
  • Svanhild Arentz Schønberg
    • 1
  1. 1.Department of Laboratory Medicine, Children’s and Women’s HealthNorwegian University of Science and Technology (NTNU)TrondheimNorway
  2. 2.Department of Mathematical SciencesNorwegian University of Science and Technology (NTNU)TrondheimNorway
  3. 3.Department of Cancer Research and Molecular MedicineNorwegian University of Science and Technology (NTNU)TrondheimNorway

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