Original Article

Lipids

, Volume 44, Issue 8, pp 673-683

First online:

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

  • Gro Leite StørvoldAffiliated withDepartment of Laboratory Medicine, Children’s and Women’s Health, Norwegian University of Science and Technology (NTNU)
  • , Karianne Giller FletenAffiliated withDepartment of Laboratory Medicine, Children’s and Women’s Health, Norwegian University of Science and Technology (NTNU)
  • , Cathrine Goberg OlsenAffiliated withDepartment of Laboratory Medicine, Children’s and Women’s Health, Norwegian University of Science and Technology (NTNU)
  • , Turid FollestadAffiliated withDepartment of Mathematical Sciences, Norwegian University of Science and Technology (NTNU)
  • , Hans Einar KrokanAffiliated withDepartment of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology (NTNU)
  • , Svanhild Arentz SchønbergAffiliated withDepartment of Laboratory Medicine, Children’s and Women’s Health, Norwegian University of Science and Technology (NTNU) Email author 

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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