The liver-brain axis of alcohol-mediated neurodegeneration: role of toxic lipids.
Alcohol abuse causes progressive toxicity and degeneration in liver and brain due to insulin resistance, which exacerbates oxidative stress and pro-inflammatory cytokine activation. Alcohol-induced steatohepatitis promotes synthesis and accumulation of ceramides and other toxic lipids that cause insulin resistance. Ceramides can readily cross the blood-brain barrier, and ceramide exposure causes neurodegeneration with insulin resistance and oxidative stress, similar to the effects of alcohol. Therefore, in addition to its direct neurotoxic effects, alcohol misuse establishes a liver-brain axis of neurodegeneration mediated by toxic lipid trafficking across the blood-brain barrier, leading to progressive white matter degeneration and cognitive impairment.
de la Monte
Suzanne M
SM
Division of Neuropathology, Brown University, Providence, RI, USA. Suzanne_DeLaMonte_MD@Brown.edu
Longato
Lisa
L
Tong
Ming
M
DeNucci
Sarah
S
Wands
Jack R
JR
D000437:Alcoholism / Q000150:complications / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002518:Ceramides / Q000096:biosynthesis; D000431:Ethanol / Q000633:toxicity; D005235:Fatty Liver, Alcoholic / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000209:etiology / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013002:Somatomedins / Q000378:metabolism
D002518:Ceramides; D007328:Insulin; D013002:Somatomedins; D000431:Ethanol; D007334:Insulin-Like Growth Factor I