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.
Anthony PinçonOlivia De MontgolfierNilay AkkoyunluCaroline DaneaultPhilippe PouliotLouis VilleneuveFrédéric LesageBernard I LevyNathalie Thorin-TrescasesÉric ThorinMatthieu RuizPublished in: Metabolites (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.
Keyphrases
- cognitive decline
- resting state
- white matter
- fatty acid
- oxidative stress
- functional connectivity
- mild cognitive impairment
- cerebral ischemia
- mouse model
- wild type
- weight loss
- dna damage
- poor prognosis
- physical activity
- multiple sclerosis
- computed tomography
- metabolic syndrome
- magnetic resonance
- middle aged
- rheumatoid arthritis
- ischemia reperfusion injury
- adipose tissue
- skeletal muscle
- endothelial cells
- signaling pathway
- blood brain barrier
- liver fibrosis