Desmosterol - Master Regulator of Lipid Metabolism

Posted on February 18, 2022


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METLIN Molecule of the Month - February 2022



Desmosterol: Master Regulator of Lipid Metabolism

Cholesterol is the sterol that gets most of the attention in human biology, however desmosterol is an underappreciated cousin. For example, desmosterol is the immediate precursor to cholesterol in one of two cholesterol biosynthesis pathways - the Bloch pathway of cholesterol biosynthesis. As the immediate precursor to cholesterol, desmosterol is structurally very similar to cholesterol with the only difference being a double bond located on the side chain between C24 and C25. Despite the similar structures of these two molecules, they have surprisingly different physiological roles, desmosterol demonstrating itself as a master regulator of lipid metabolism.

Desmosterol dominant ligand of liver X receptor (LXR): Nearly one decade ago (Spann, et. al., 2012), desmosterol was identified as the dominant liver x receptor (LXR) ligand formed in macrophage foam cells. The same study found that desmosterol has several functions in macrophages such as integration of cholesterol and fatty acid synthesis and inhibition of inflammatory responses. In 2018, a further study indicated cell-specific differences in LXR responses to desmosterol and its synthetic mimetics in macrophages and liver cells (Muse, et. al., 2018).

Desmosterol DHCR24 reduction inhibition as an inflammation drug target: Inhibiting the enzymatic reduction of desmosterol has a beneficial cascade effect (Körner, et.al., 2019). This study investigated the possibility of alleviating inflammation via inhibition of Δ24-dehydrocholesterol reductase (DHCR24), the enzyme responsible for reducing desmosterol to cholesterol. Lipidomic analysis revealed that endogenous biosynthesis of polyunsaturated fatty acids (PUFAs) was significantly increased after inhibition of DHCR24. PUFAs are known precursors for specialized pro-resolving mediators and other anti-inflammatory lipids. To see if the increased production of PUFAs also lead to increased production of anti-inflammatory lipids, they monitored the concentrations of several known mediators of inflammation including 19,20-epoxydocosapentaenoic acid (19,20-EpDPA), 19,20-dihydroxydocosapentaenoic acid (DiHDPA), and prostaglandin E2. Each of these molecules had increased concentrations 4 hours after inhibition, giving credibility to the hypothesis that the inhibition of DHCR24 is a viable pathway to inflammation resolution. Thus, maintaining desmosterol levels lead to alleviating inflammation.

Desmosterol repairing demyelination, an LXR and DHCR24 dance: More recently (Berghoff, et.al., 2021) it was found that desmosterol plays an important role in repairing inflamed, demyelinated lesions, most notably found in multiple sclerosis patients. It was previously hypothesized that cholesterol played an important role in this process due to 70% of brain cholesterol being associated with myelin. This hypothesis was correct in that a sterol does play an important role, however the sterol is instead the LXR ligand and precursor to cholesterol, desmosterol. So, how does desmosterol aid repair of demyelinated lesions? When myelin is degenerated, a lot of cholesterol needs to be scavenged. Microglia and macrophages take up the large amounts of cholesterol found in the myelin debris. Pro-inflammatory milieu promotes cholesterol synthesis, and all sterol synthesizing enzymes were found to be upregulated, other than DHCR24. And, as you recall from earlier in this article, DHCR24 transforms desmosterol into cholesterol. If desmosterol production is upregulated without the upregulation of DHCR24, this leads to a higher concentration of desmosterol being present. This activates LXR signalling, which stimulates genes for cholesterol recycling and suppresses the pro-inflammatory phenotype. These two actions promote remyelination.

Avanti and METLIN: If you are interested in desmosterol, visit Avanti. We also offer deuterated and ester derivatives of this desmosterol for expanded studies. And, to see MS/MS and neutral loss data on desmosterol and 860,000 other molecular standards, visit the METLIN Gen2 database.