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

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.

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Abbreviations

Aβ:

amyloid beta

AβPP:

amyloid beta precursor protein

AD:

Alzheimer’s disease

BACE1:

β-site AβPP cleaving enzyme 1

CHOP:

C/EBP homologous protein

ChIP:

chromatin immunoprecipitation

ER:

endoplasmic reticulum

LXRα:

liver X receptor alpha

N2a:

Neuro-2a mouse neuroblastoma cells

NCoA:

nuclear receptor coactivator

NFT:

neurofibrillary tangles

PA:

palmitic acid

sFFA:

saturated free fatty acids

SRC:

steroid receptor coactivator

SRE:

sterol response element

SREBP:

sterol response element binding protein

WB:

western blotting

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Funding

This work was supported by a Grant from the National Institute of Health (R01AG045264) to Dr. Othman Ghribi.

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Correspondence to Othman Ghribi.

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All animal procedures and studies carried out were approved by the Institutional Animal Care and Use Committee at the University of North Dakota. All animal procedures and studies were carried out in accordance with the U.S Public Health Service’s “Policy on Humane Care and Use of Laboratory Animals” and “Guide for the Care and Use of Laboratory Animals”. All animal procedures and studies carried out are in compliance with the U.S National Research Council’s “Guide for the Care and Use of Laboratory Animals.”

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Marwarha, G., Claycombe-Larson, K., Lund, J. et al. Palmitate-Induced SREBP1 Expression and Activation Underlies the Increased BACE 1 Activity and Amyloid Beta Genesis. Mol Neurobiol 56, 5256–5269 (2019). https://doi.org/10.1007/s12035-018-1451-8

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Keywords

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