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Saturated fat‐enriched diet decreases SIRT1 expression in the mouse hippocampus ‐ The SIRTain effects of saturated fat in the brain
Author(s) -
Marwarha Gurdeep,
Ghribi Othman
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.lb7
Subject(s) - sirtuin 1 , endocrinology , medicine , hippocampus , chop , hippocampal formation , biology , transcription factor , neuroscience , endoplasmic reticulum , microbiology and biotechnology , genetics , downregulation and upregulation , gene
A multitude of prospective cohort epidemiological studies have posited a direct positive correlation between saturated fat‐enriched diets and an increased risk for cognitive impairment, deficits in learning and memory, leading to enhanced susceptibility for the development and progression of neurodegenerative disorders such as Alzheimer's disease (AD). Our previous studies have shown that saturated‐fat enriched diet cause an increase in BACE1 expression and activity leading to an increase in Amyloid‐beta burden in the brains of the C57BL/6J wild‐type mice (1–3). The histone deacetylase and the sirtuin SIRT1, is a master regulator of molecular processes that regulate lifespan and aging, the primary risk factor for AD. A plethora of laboratory studies have demonstrated the indispensable role of SIRT1 in regulating and maintaining synaptic integrity as well as synaptic plasticity at the molecular level and cognitive processes that underlie learning and memory. Herein, we show that feeding nine‐month old C57BL/6J wild‐type mice, a palmitate‐enriched diet for three months, elicits a profound attenuation of SIRT1 expression in the hippocampal region of the brain. Exogenous palmitate treatment of human SH‐SY5Y neuroblastoma cells also results in an attenuation of SIRT1 expression. We further elucidated and delineated the underlying signaling and molecular mechanisms involved and discovered a deleterious role of the palmitate‐evoked Endoplasmic Reticulum (ER) stress‐induced transcription factor C/EBP Homologous Protein (CHOP) in mediating the palmitate effects on SIRT1 expression. Homozygous Chop −/− knock‐out mice fed a palmitate‐enriched diet did not exhibit the same degree of loss of basal SIRT1 expression in the brain compared to their C57BL/6J wild‐type littermates. Also, RNA‐interference mediated knock‐down of CHOP expression in SH‐SY5Y neuroblastoma cells rescued the palmitate‐induced deficits in SIRT1 expression. Further insight into the mechanisms unveiled the role of CHOP in transcriptional repression of SIRT1 expression executed through the negative regulation of the transcription factor C/EBPα. Our study unveils SIRT1 as a unique molecular target that is negatively regulated by palmitate‐enriched diets. Further studies are warranted to determine the potential biochemical and physiological impact of this palmitate‐induced attenuation of SIRT1 expression, a histone deacetylase that plays an indispensable role in the regulation of cognitive processes and aging at the molecular level. Support or Funding Information This work was supported by a Grant from the NIH (R01AG045264) to Dr. Othman Ghribi. The authors declare that they have no competing interests. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .