Histone Deacetylase Inhibition Decreases Cholesterol Levels in Neuronal Cells by Modulating Key Genes in Cholesterol Synthesis, Uptake and Efflux

Abstract

Cholesterol is an essential component of the central nervous system and increasing evidence suggests an association between brain cholesterol metabolism dysfunction and the onset of neurodegenerative disorders. Interestingly, histone deacetylase inhibitors (HDACi) such as trichostatin A (TSA) are emerging as promising therapeutic approaches in neurodegenerative diseases, but their effect on brain cholesterol metabolism is poorly understood. We have previously demonstrated that HDACi up-regulate CYP46A1 gene transcription, a key enzyme in neuronal cholesterol homeostasis. In this study, TSA was shown to modulate the transcription of other genes involved in cholesterol metabolism in human neuroblastoma cells, namely by up-regulating genes that control cholesterol efflux and down-regulating genes involved in cholesterol synthesis and uptake, thus leading to an overall decrease in total cholesterol content. Furthermore, co-treatment with the amphipathic drug U18666A that can mimic the intracellular cholesterol accumulation observed in cells of Niemman-Pick type C patients, revealed that TSA can ameliorate the phenotype induced by pathological cholesterol accumulation, by restoring the expression of key genes involved in cholesterol synthesis, uptake and efflux and promoting lysosomal cholesterol redistribution. These results clarify the role of TSA in the modulation of neuronal cholesterol metabolism at the transcriptional level, and emphasize the idea of HDAC inhibition as a promising therapeutic tool in neurodegenerative disorders with impaired cholesterol metabolism.

Normalization of Hepatic Homeostasis in the Npc1 Mouse Model of Niemann-Pick Type C Disease Treated with the Histone Deacetylase Inhibitor Vorinostat

“…The Hmgcs1, Hmgcr, Mvk, Mvd, Idi1, Lss, Cyp51, and Ldlr genes were repressed by vorinostat only in the Npc1 nmf164 mice, reflecting the successful treatment of hepatic NP-C disease as well as a therapeutic mechanism that is independent of Npc1. Interestingly, HDAC inhibitors have also been shown to repress expression of cholesterol homeostatic genes in U18666A-treated SH-SY5Y human neuroblastoma cells (54). HDAC inhibitors can further impact expression of the genome by directing recovery of misfolded mutated proteins via the induction of chaperone pathways (7).…”

Niemann-Pick C disease and mobilization of lysosomal cholesterol by cyclodextrin

“…One of the most promising is inhibition of histone deacetylases (HDACs). HDACs appear to play important roles in neuronal survival ( 158,159 ). HDAC inhibitors have already been approved for clinical use in humans for treatment of certain cancers.…”

Correction of Niemann-Pick type C1 disease with the histone deacetylase inhibitor valproic acid

“…While HDACis have been shown to have positive effects on the folding, trafficking and function of NPC1 (18,60,128), they have also been linked to restoring WT-like expression profiles for lipid biosynthetic components, including enzymes involved in cholesterol biosynthesis (129)(130)(131), which are dysregulated in NPC1 disease (132). Most notably, SAHA has been shown to normalize the NPC-associated elevation in gene expression related to cholesterol biosynthesis, including the sterol regulatory element binding factor 2 (SREB2), a transcription factor that regulates cholesterol biosynthesis components, as well as the expression of Hmgcs1, Hmgcr, Mvk, Mvd, Idi1, Lss and Cyp51 (130).…”