Treatment with a naturally occurring cholesterol-derived compound, called 25-hydroxycholesterol (25-HC), may represent a new strategy to prevent the accumulation of long-chain fatty molecules in X-linked adrenoleukodystrophy (X-ALD), results from a preclinical study suggest.
The findings were reported in an article titled “Exogenous Addition of 25-Hydroxycholesterol Reduces Level of Very Long-Chain Fatty Acids in X-Linked Adrenoleukodystrophy,” published in the journal ChemistryOpen.
X-ALD is metabolic disease that affects different parts of the nervous system. It is caused by mutations in a gene that encodes an important enzyme that regulates the metabolism of fatty molecules called very long-chain fatty acids (VLCFAs).
Impaired breakdown of these VLCFAs makes them accumulate around the protective myelin sheath of nerve cells, affecting the cells’ normal activity and communication. As a result, patients with X-ALD experience cognitive limitations, movement problems, and hormonal changes.
Damage to brain cells triggered by inflammation is the main manifestation of childhood cerebral adrenoleukodystrophy (CCALD), the most severe form of X-ALD.
In a previous study, researchers found that stem cells from CCALD patients produced more 25-HC and its synthesizing enzyme, called cholesterol 25-hydroxylase (or CH25H). Collectively, the study data demonstrated that 25-HC is an important mediator of neuroinflammation in CCALD.
To better understand the role of 25-HC in disease, the team conducted further experiments using stem cells and fibroblasts (connective tissue cells) derived from CCALD patients.
Results showed that when these cells were exposed to higher levels of 25-HC, the levels of VLCFAs would effectively decrease.
The team then genetically manipulated these cells to either induce or block the production of the CH25H enzyme. With this approach, researchers found that higher levels of CH25H enzyme led to a slight decrease in VLCFA levels, while blocking the production of the enzyme led to a significant increase in accumulated VLCFAs.
However, the effects of higher levels of 25-HC had a stronger impact on VLCFA metabolism than the levels of CH25H enzyme, contributing to the suppression of VLCFA accumulation.
Further experiments revealed that the therapeutic effect of 25-HC may occur through the inhibition of the ELOVL1 gene, an enzyme that extends VLCFA’s length. Also, activation of a 25-HC liver receptor, called liver X receptor (LXR), with a chemical compound led to significant reduction in VLCFAs in normal human skin fibroblasts, as well as in CCALD-derived cells.
“It seems that 25-HC may act on multiple targets … to reduce VLCFA levels,” researchers said. “We believe that a novel therapeutic agent for X-ALD could be discovered from small molecules derived from 25-HC.”
The team said additional studies are warranted to better understand the role and impact of 25-HC and determine its full therapeutic potential to treat X-ALD.