Bile acid biosynthesis in Smith-Lemli-Opitz syndrome bypassing cholesterol: Potential importance of pathway intermediates. Issue 206 (February 2021)

• Record Type: Journal Article
• Authors: Abdel-Khalik, Jonas; Hearn, Thomas; Dickson, Alison L.; Crick, Peter J.; Yutuc, Eylan; Austin-Muttitt, Karl; Bigger, Brian W.; Morris, Andrew A.; Shackleton, Cedric H.; Clayton, Peter T.; Iida, Takashi; Sircar, Ria; Rohatgi, Rajat; Marschall, Hanns-Ulrich; Sjövall, Jan; Björkhem, Ingemar; Mullins, Jonathan G.L.; Griffiths, William J.; Wang, Yuqin
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 206(2021)
• Publication Date: 2021-02
• Subjects: SLOS Smith-Lemli-Opitz syndrome -- 7-DHC 7-dehydrocholesterol -- LC–MS liquid chromatography – mass spectrometry -- Smo smoothened (FZD11) -- Hh hedgehog -- CYP cytochrome P450 -- CYP7A1 cytochrome P450 family 7 subfamily A member 1 -- CYP27A1 cytochrome P450 family 27 subfamily A member 1 -- 26−HC (25R)26-hydroxycholesterol -- 27−HC 27-hydroxycholesterol -- CH25H cholesterol 25-hydroxylase -- CYP46A1 cytochrome P450 family 46 subfamily A member 1 -- FXR farnasoid X receptor -- LXR liver X receptor -- PXR pregnane X receptor -- VDR vitamin D receptor -- CAR constitutive androstane receptor -- GPCR G protein-coupled receptor -- GPR183 Epstein Barr virus induced gene 2 (EBI2) -- GPBAR1 G protein-coupled bile acid receptor 1 -- NMDAR N-methyl-d-aspartate receptor -- CSF cerebrospinal fluid -- CNS central nervous system -- 3β 7α-diHCA, 3β, 7α-dihydroxycholest-5-en-(25R)26-oic acid -- CTX cerebrotendinous xanthomatosis -- DHCR7 7-dehydrocholesterol reductase -- 25H 7O-C, 3β, 25-dihydroxycholest-5-en-7-one -- 7β 25-diHC, 7β, 25-dihydroxycholesterol -- 26H 7O-C, 3β, 26-dihydroxycholest-5-en-7-one -- 7β 26-diHC, 7β, 26-dihydroxycholesterol -- 3βH 7O-CA, 3β-hydroxy-7-oxocholest-5-en-(25R)26-oic acid -- 3β 7β-diHCA, 3β, 7β-dihydroxycholest-5-en-26-oic -- 3β 7β, 24-triHCA, 3β, 7β, 24-trihydroxycholest-5-en-26-oic -- 3β 7β, 25-triHCA, 3β, 7β, 25-trihydroxycholest-5-en-26-oic -- 3βH 7O-Δ5-BA, 3β-hydroxy-7-oxochol-5-en-24-oic -- 3β 7β-diH-Δ5-BA, 3β, 7β-dihydroxychol-5-en-24-oic -- MSn multistage fragmentation -- GlcNAc N-acetylglucosamine -- NP-C Niemann-Pick disease type C -- DHCR24 24-dehydrocholesterol reductase -- HSD11B1 hydroxysteroid (11-beta) dehydrogenase 1 (short chain dehydrogenase/reductase family 26C member 1) -- HSD11B2 hydroxysteroid dehydrogenase (11-beta) 2 (short chain dehydrogenase/reductase family 9C, member 3) -- BACS bile acyl CoA-synthetase (SLC27A5, solute carrier family 27 member 5) -- AMACR alpha-methylacyl-CoA-racemase -- ACOX2 peroxisomal acyl-coenzyme A oxidase 2 -- DBP peroxisomal multifunctional enzyme type 2 or HSD17B4 -- SPCx sterol carrier protein x or sterol carrier protein 2 -- ACOT acyl-CoA thioesterase -- UGT3A1 7β-hydroxy bile acid UDP N-acetylglucosaminyl transferase -- SULT2A1 sulfotransferase family 2A member 1 -- BAAT bile acid-CoA:amino acid N-acyltransferase -- CRD cysteine rich domain -- 7−OC 7-oxocholesterol -- 7β−HC 7β-hydroxycholesterol -- GP Girard P -- HSD3B7 3β-Hydroxy-Δ5-C27-steroid oxidoreductase (short chain dehydrogenase/reductase family 11E, member 3) -- Ptch1 Patched-1 -- SHH Sonic hedgehog -- Gli1 GLI family zinc finger 1 -- 20S−HC 20S-hydroxycholesterol -- LD linker domain -- TMD transmembrane domain -- ECL3 extracellular loop 3 -- zSmo zebrafish Smo -- SDS sodium dodecyl sulfate -- DTT dithiothreitol -- DSX DrugScore eXtended; Sterol -- Oxysterol -- Bile acid -- 7-dehydrocholesterol -- Smith-Lemli-Opitz syndrome -- High-Performance liquid chromatography -- Mass spectrometry -- Hedgehog signalling pathway; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2020.105794
• Languages: English
• ISSNs: 0960-0760

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. Abstract: Bile acids are the end products of cholesterol metabolism secreted into bile. They are essential for the absorption of lipids and lipid soluble compounds from the intestine. Here we have identified a series of unusual Δ 5 -unsaturated bile acids in plasma and urine of patients with Smith-Lemli-Opitz syndrome (SLOS), a defect in cholesterol biosynthesis resulting in elevated levels of 7-dehydrocholesterol (7-DHC), an immediate precursor of cholesterol. Using liquid chromatography – mass spectrometry (LC–MS) we have uncovered a pathway of bile acid biosynthesis in SLOS avoiding cholesterol starting with 7-DHC and proceeding through 7-oxo and 7β-hydroxy intermediates. This pathway also occurs to a minor extent in healthy humans, but elevated levels of pathway intermediates could be responsible for some of the features SLOS. The pathway is also active in SLOS affected pregnancies as revealed by analysis of amniotic fluid. Importantly, intermediates in the pathway, 25-hydroxy-7-oxocholesterol, (25R)26-hydroxy-7-oxocholesterol, 3β-hydroxy-7-oxocholest-5-en-(25R)26-oic acid and the analogous 7β-hydroxysterols are modulators of the activity of Smoothened (Smo), an oncoprotein that mediates Hedgehog (Hh) signalling across membranes during embryogenesis and in the regeneration of postembryonic tissue. Computational docking of the 7-oxo and 7β-hydroxy compounds to the extracellular cysteine rich domain of Smo reveals that they bind in the same groove as both 20S-hydroxycholesterol and cholesterol, known activators of the Hh pathway.