The Lipidomic Signature of Alcohol-Related Brain Injury

Abstract

Alcohol use disorder (AUD) is a diagnosis characterised by psychosocial behaviours manifesting from chronic alcohol misuse. The effects of chronic alcohol misuse on the brain are widespread and are often described as alcohol-related brain injury (ARBI). Lipid-rich brain structures are particularly vulnerable to alcohol toxicity, reflected by decreased white matter volume and integrity and localised neuron loss in heavy alcohol users. This thesis aims to understand the effect AUD has on lipids in the brain. Using brain samples from a cohort of 20 donors with AUD and 20 controls, the first study utilises liquid chromatography/mass spectrometry (LC/MS) techniques to describe which lipid classes are particularly affected in ARBI across the white and grey matter of three brain regions (prefrontal cortex, middle temporal gyrus, and the primary visual cortex). A significant finding was that sphingolipids and some glycerophospholipids decreased in both prefrontal and primary visual cortices in AUD cases. In addition, fatty acids were generally shorter in carbon chain length and had reduced double bonds. To continue this characterisation, enzymes that synthesise sphingolipids were assayed by western blotting, which revealed an increase in ceramide transport (CERT) protein levels, a protein that shuttles ceramide between organelles to be converted into other sphingolipids. Next, neuron loss has been previously described in the prefrontal but not the visual cortex from donors with AUD, so immunohistochemistry and cell counting software was used to quantify neurons in both cortices of this cohort. expressed genes, whose products are involved in lipid metabolism. The findings revealed significantly enriched pathways relating to lipid metabolism and peroxisome proliferator-activated receptor (PPAR) signalling in AUD cases with liver cirrhosis but not steatosis or in the absence of pathology.