Expression profiles of cholesterol metabolism-related genes are altered during development of experimental autoimmune encephalomyelitis in the rat spinal cord

Abstract

Increased evidence suggests that dysregulation of cholesterol metabolism may be a key event contributing to progression of multiple sclerosis (MS). Using an experimental autoimmune encephalomyelitis (EAE) model of MS we revealed specific changes in the mRNA and protein expression of key molecules involved in the maintaining of cholesterol homeostasis in the rat spinal cord: 3-hydroxy-3-methylglutaryl-coenzyme-A reductase (HMGCR), apolipoprotein E (ApoE) and cholesterol 24-hydroxylase (CYP46A1) during the course of disease. The presence of myelin lipid debris was seen only at the peak of EAE in demyelination loci being efficiently removed during the recovery period. Since CYP46A1 is responsible for removal of cholesterol excess, we performed a detailed profiling of CYP46A1 expression and revealed regional and temporal specificities in its distribution. Double immunofluorescence staining demonstrated CYP46A1 localization with neurons, infiltrated macrophages, microglia and astrocytes in the areas of demyelination, suggesting that these cells play a role in cholesterol turnover in EAE. We propose that alterations in the regulation of cholesterol metabolism at the onset and peak of EAE may add to the progression of disease, while during the recovery period may have beneficial effects contributing to the regeneration of myelin sheath and restoration of neuronal function.

Dysregulated bile acid synthesis and dysbiosis are implicated in Western diet–induced systemic inflammation, microglial activation, and reduced neuroplasticity

“…Moreover, CYP27A1 mutation leads to neurologic dysfunction (94). Cholesterol is exported from the brain by converting into 24( S )‐hydroxycholesterol using CYP46A1 (95). Mice deficient in CYP46A1 have impaired learning and defective hippocampal LTP (96).…”

Upregulation of cholesterol 24-hydroxylase following hypoxia–ischemia in neonatal mouse brain

“…Although primarily confined to neurons in the healthy brain, CYP46A1 has been found in other cell types in different disease conditions, for example, in activated microglia and reactive astrocytes in brain trauma ( 17 , 18 ), in astrocytes of Alzheimer disease patients ( 31 ), or in macrophages/microglia in an animal model of multiple sclerosis ( 32 ). They were proposed to clear extracellular cholesterol released from the damaged cell membranes, which has not been proved experimentally.…”

LXR alters CD4+ T cell function through direct regulation of glycosphingolipid synthesis

“…To determine whether LXR regulates UGCG expression by directly binding to the UGCG locus, we screened for potential LXR response element (LXRE) sequences in silico. A putative DR4 sequence was identified upstream of the UGCG gene that coincided with an LXR-binding peak in HT29 cells treated with GW 27 (Fig. S2g).…”