Next Article in Journal
Exo-Metabolites of Phaseolus vulgaris-Nodulating Rhizobial Strains
Next Article in Special Issue
Oxylipin Profiling of Alzheimer’s Disease in Nondiabetic and Type 2 Diabetic Elderly
Previous Article in Journal
MetPC: Metabolite Pipeline Consisting of Metabolite Identification and Biomarker Discovery Under the Control of Two-Dimensional FDR
Open AccessArticle

Non-Alcoholic Fatty Liver Disease, and the Underlying Altered Fatty Acid Metabolism, Reveals Brain Hypoperfusion and Contributes to the Cognitive Decline in APP/PS1 Mice

1
Department of Pharmacology and Physiology, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada
2
Research Center, Montreal Heart Institute, University of Montreal, Montreal, QC H1T 1C8, Canada
3
Department of Electrical Engineering, Ecole Polytechnique de Montréal, Montreal, QC H3T 1J4, Canada
4
Institut des Vaisseaux et du Sang, Hôpital Lariboisière, 75010 Paris, France
5
Department of Surgery, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada
6
Department of Medecine, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada
*
Author to whom correspondence should be addressed.
Current address: Campus Pierre et Marie Curie, Sorbonne Université, 4 place Jussieu, 75005 Paris, France.
These authors contributed equally to this work.
Metabolites 2019, 9(5), 104; https://doi.org/10.3390/metabo9050104
Received: 29 April 2019 / Revised: 16 May 2019 / Accepted: 21 May 2019 / Published: 25 May 2019
Non-alcoholic fatty liver disease (NAFLD), the leading cause of chronic liver disease, is associated with cognitive decline in middle-aged adults, but the mechanisms underlying this association are not clear. We hypothesized that NAFLD would unveil the appearance of brain hypoperfusion in association with altered plasma and brain lipid metabolism. To test our hypothesis, amyloid precursor protein/presenilin-1 (APP/PS1) transgenic mice were fed a standard diet or a high-fat, cholesterol and cholate diet, inducing NAFLD without obesity and hyperglycemia. The diet-induced NAFLD disturbed monounsaturated and polyunsaturated fatty acid (MUFAs, PUFAs) metabolism in the plasma, liver, and brain, and particularly reduced n-3 PUFAs levels. These alterations in lipid homeostasis were associated in the brain with an increased expression of Tnfα, Cox2, p21, and Nox2, reminiscent of brain inflammation, senescence, and oxidative stress. In addition, compared to wild-type (WT) mice, while brain perfusion was similar in APP/PS1 mice fed with a chow diet, NAFLD in APP/PS1 mice reveals cerebral hypoperfusion and furthered cognitive decline. NAFLD reduced plasma β40- and β42-amyloid levels and altered hepatic but not brain expression of genes involved in β-amyloid peptide production and clearance. Altogether, our results suggest that in a mouse model of Alzheimer disease (AD) diet-induced NAFLD contributes to the development and progression of brain abnormalities through unbalanced brain MUFAs and PUFAs metabolism and cerebral hypoperfusion, irrespective of brain amyloid pathology that may ultimately contribute to the pathogenesis of AD. View Full-Text
Keywords: NAFLD; inflammation; polyunsaturated fatty acids; senescence; brain hypoperfusion; untargeted and targeted lipidomics; amyloïd Beta; liver-to-brain axis; Alzheimer disease mouse model NAFLD; inflammation; polyunsaturated fatty acids; senescence; brain hypoperfusion; untargeted and targeted lipidomics; amyloïd Beta; liver-to-brain axis; Alzheimer disease mouse model
Show Figures

Figure 1

MDPI and ACS Style

Pinçon, A.; De Montgolfier, O.; Akkoyunlu, N.; Daneault, C.; Pouliot, P.; Villeneuve, L.; Lesage, F.; Levy, B.I.; Thorin-Trescases, N.; Thorin, É.; Ruiz, M. Non-Alcoholic Fatty Liver Disease, and the Underlying Altered Fatty Acid Metabolism, Reveals Brain Hypoperfusion and Contributes to the Cognitive Decline in APP/PS1 Mice. Metabolites 2019, 9, 104.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop