Abstract
Every cell in vertebrates possesses the machinery to synthesise cholesterol and to metabolise it. The major route of cholesterol metabolism is conversion to bile acids. Bile acids themselves are interesting molecules being ligands to nuclear and G protein‐coupled receptors, but perhaps the intermediates in the bile acid biosynthesis pathways are even more interesting and equally important. Here, we discuss the biological activity of the different intermediates generated in the various bile acid biosynthesis pathways. We put forward the hypothesis that the acidic pathway of bile acid biosynthesis has primary evolved to generate signalling molecules and its utilisation by hepatocytes provides an added bonus of producing bile acids to aid absorption of lipids in the intestine.
Highlights
Cholesterol metabolism has been studied for many decades [1,2,3]
While bile acids and steroid hormones are of undoubted importance, in recent years interest has shifted to intermediates in their biosynthesis and to a category of molecules known as oxysterols [6,7,8,9]
The biological activities of 24S-HC and 24S,25-EC appear to overlap in that both activate liver X receptor (LXR), inhibit cholesterol biosynthesis via insulin-induced gene (INSIG) and repression of sterol regulatory-binding protein-2 (SREBP-2) processing, and both are ligands to Smo. 24S-HC and 24S,25-EC are abundant in brain, and we speculate that brain biology has built a layer of redundancy in that CYP46A1 expressed in neurons and squalene epoxidase (SQLE) expressed in glia can each direct synthesis of the biologically active 24S-oxidised sterols, that is 24S-HC and 24S,25-HC, respectively
Summary
Cholesterol metabolism has been studied for many decades [1,2,3]. In mammals, the products of cholesterol metabolism are bile acids, and steroid hormones and their metabolites [4,5]. In support of the hypothesis of Zang et al [29] that blocking cholesterol export from late endosomes/lysosomes inhibits viral replication, Carpinteiro et al [50] have recently found that inhibiting acid sphingomyelinase prevents SARSCoV-2 uptake by epithelial cells, their explanation for the involvement of acid sphingomyelinase in SARS-CoV-2 infection was at the level of ceramide in the outer leaflet of the plasma membrane. A combination of both mechanisms would suggest that 25-HC can block membrane fusion and viral entry by reducing the available nonesterified cholesterol in membranes by inhibiting transport of cholesterol out of the late endosome/lysosome compartment and through activation of acyl-CoA cholesterol acyltransferase. It is interesting to note that neither of the antiviral mechanisms discussed above invoked inhibition of SREBP-2 (sterol regulatory-binding protein-2) processing or activation of LXRs, two key regulators of cellular cholesterol status. It is interesting to note that total 25-HC (sum of biologically active nonesterified 25-HC and its inactive esterified form) is elevated in patients suffering mild SARS-CoV-2 [28], suggesting the successful defence against the virus by 25-HC may be via its enhanced biosynthesis
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