Palmitate-Induced SREBP1 Expression and Activation Underlies the Increased BACE 1 Activity and Amyloid Beta Genesis

Gurdeep Marwarha, Kate Claycombe-Larson, Jonah Lund, Ghribi Othman

Research output: Contribution to journalArticle

Abstract

Numerous cross-sectional and longitudinal studies have implicated saturated fat-enriched diets in the etio-pathogenesis of Alzheimer’s disease (AD). Emerging evidence shows that saturated fat-enriched diets, such as palmitate-enriched diets, increase amyloid-beta (Aβ) production, the histopathological hallmark of AD. However, the molecular mechanisms that underlie the deleterious effects of palmitate-enriched diets in the augmentation of Aβ genesis are yet to be characterized. Sterol response element binding protein 1 (SREBP1) is a transcription factor that is modulated by saturated fatty acids, such as palmitate, and consequently regulates the expression of genes that code for proteins involved in almost all facets of lipid metabolism. Herein, we determined the role of changes in SREBP1 expression and transcriptional activity in the palmitate-induced effects on Aβ genesis and BACE1 expression, the enzyme that catalyzes the rate-limiting step in Aβ biosynthesis. We demonstrate that palmitate-induced SREBP1 activation directly regulates BACE1 expression at the transcriptional level in the mouse hippocampus and mouse Neuro-2a (N2a) neuroblastoma cells. Chromatin immunoprecipitation (ChIP) studies show that palmitate increases the binding of SREBP1 to the Bace1 promoter region in the mouse hippocampus and mouse N2a neuroblastoma cells. Ectopic expression of the dominant negative SREBP1 mutant and knocking-down SREBP1 expression significantly reduced the palmitate-induced increase in BACE1 expression and subsequent Aβ genesis in mouse N2a neuroblastoma cells. Our study unveils SREBP1 activation as a novel molecular player in the palmitate-induced upregulation of BACE1 expression and subsequent Aβ genesis.

Original languageEnglish (US)
Pages (from-to)5256-5269
Number of pages14
JournalMolecular Neurobiology
Volume56
Issue number7
DOIs
StatePublished - Jul 1 2019

Fingerprint

Palmitates
Response Elements
Sterols
Amyloid
Carrier Proteins
Neuroblastoma
Diet
Hippocampus
Alzheimer Disease
Fats
Chromatin Immunoprecipitation
Lipid Metabolism
Genetic Promoter Regions
Longitudinal Studies
Transcription Factors
Up-Regulation
Fatty Acids
Cross-Sectional Studies
Enzymes

Keywords

  • Alzheimer’s disease
  • BACE 1
  • Palmitate
  • SREBP1
  • Saturated free fatty acids

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

Palmitate-Induced SREBP1 Expression and Activation Underlies the Increased BACE 1 Activity and Amyloid Beta Genesis. / Marwarha, Gurdeep; Claycombe-Larson, Kate; Lund, Jonah; Othman, Ghribi.

In: Molecular Neurobiology, Vol. 56, No. 7, 01.07.2019, p. 5256-5269.

Research output: Contribution to journalArticle

Marwarha, Gurdeep ; Claycombe-Larson, Kate ; Lund, Jonah ; Othman, Ghribi. / Palmitate-Induced SREBP1 Expression and Activation Underlies the Increased BACE 1 Activity and Amyloid Beta Genesis. In: Molecular Neurobiology. 2019 ; Vol. 56, No. 7. pp. 5256-5269.
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