Bile acid biosynthesis in Smith-Lemli-Opitz syndrome bypassing cholesterol: Potential importance of pathway intermediates

Abstract

Highlights New pathway of bile acid biosynthesis avoiding cholesterol. Mechanism for biosynthesis of 3β,7β-dihydroxy-5-ene bile acids. Biosynthesis of 3β-hydroxy-7-oxo-5-ene bile acids. Pathway intermediates bind to and activate Smo. A new link between SLOS and deranged Hh signalling.

Sterols, Oxysterols, and Accessible Cholesterol: Signalling for Homeostasis, in Immunity and During Development

“…However, oxysterols have roles beyond cholesterol per se and can act as ligands to G proteincoupled receptors (GPCR; Hannedouche et al, 2011;Liu et al, 2011). One GPCR that oxysterols and cholesterol activate is Smoothened (SMO), a critical receptor in the Hedgehog (Hh) signalling pathway (Abdel-Khalik et al, 2020;Radhakrishnan et al, 2020). Like in cholesterol regulation and in protection against microbial infection, oxysterols and accessible cholesterol are closely linked in the Hh signalling pathway.…”

“…The components for Hh signalling are found in primary cilia, antenna-like organelles which are continuous with the plasma membrane (Rohatgi et al, 2007). Side-chain oxysterols are potential second messengers in the Hh pathway, in that they activate Hh signalling in cultured cells, even in the absence of SHH, and induce the accumulation of SMO in primary cilia (Corcoran and Scott, 2006;Dwyer et al, 2007;Nachtergaele et al, 2012;Abdel-Khalik et al, 2020). Side-chain oxysterols bind to the extracellular cysteine-rich domain (CRD) of SMO (Myers et al, 2013;Nachtergaele et al, 2013;Nedelcu et al, 2013;Abdel-Khalik et al, 2020) and have also been found to be enriched in primary cilia (Raleigh et al, 2018).…”

“…Side-chain oxysterols are potential second messengers in the Hh pathway, in that they activate Hh signalling in cultured cells, even in the absence of SHH, and induce the accumulation of SMO in primary cilia (Corcoran and Scott, 2006;Dwyer et al, 2007;Nachtergaele et al, 2012;Abdel-Khalik et al, 2020). Side-chain oxysterols bind to the extracellular cysteine-rich domain (CRD) of SMO (Myers et al, 2013;Nachtergaele et al, 2013;Nedelcu et al, 2013;Abdel-Khalik et al, 2020) and have also been found to be enriched in primary cilia (Raleigh et al, 2018). Cholesterol also binds to the CRD of SMO and has been considered as the second messenger between PTCH1 and SMO (Byrne et al, 2016;Luchetti et al, 2016).…”

“…Side-chain oxysterols bind to and activate SMO in cultured cells (Corcoran and Scott, 2006;Dwyer et al, 2007;Nachtergaele et al, 2012;Myers et al, 2013;Nedelcu et al, 2013;Raleigh et al, 2018;Abdel-Khalik et al, 2020). Could oxysterols and cholesterol work in concert with one molecule occupying the CRD pocket and the other the TMD and together promote maximum signalling?…”

“…This is not an unreasonable concept as Smith-Lemli-Opitz syndrome (SLOS) which presents with dysmorphology consistent with defective Hh signalling is accompanied by reduced cholesterol biosynthesis and an unusual pattern of oxysterols. Some of the SLOS derived oxysterols which are modified in both the sterol side-chain and ring fit into the CRD binding pocket of SMO and activate Hh signalling, but are perhaps less efficient activators than simple side-chain oxysterols, resulting in reduced Hh signalling during development of the SLOS embryo compared to that experienced during normal development (Abdel-Khalik et al, 2020). In addition, there is good evidence that oxysterols oxidised in the ring and side-chain activate SMO in the context of medulloblastoma (Raleigh et al, 2018).…”