|Figure 5: Metabolites of the cholesterol biosynthetic pathway function as endogenous RORγ agonists.
A. Shown is a schematic view of the cholesterol synthetic pathway. Zymosterol and
desmosterol are among the RORγ agonists with the highest affinity. Deficiency in Fdft1
or Cyp51A1, enzymes acting upstream in the cholesterol biosynthetic pathway, inhibit
the synthesis of downstream RORγ agonists subsequently leading to reduced RORγt activation
and Th17 differentiation. FDT1, Farnesyl-Diphosphate Farnesyltransferase 1; SQLE,
Squalene Epoxidase; LSS, Lanosterol Synthase; TM7SF2, Transmembrane 7 Superfamily
Member 2 (C-14 Sterol Reductase); FAXDC2/SC4MOL, Fatty Acid Hydroxylase Domain Containing
2/Methylsterol Monooxygenase 1; NSDHL, NAD(P) Dependent Steroid Dehydrogenase-Like;
HSD17B7, Hydroxysteroid (17-Beta) Dehydrogenase 7; EBP, Emopamil Binding Protein (Sterol
Isomerase); SC5D, Sterol-C5-Desaturase; DHCR7, 7-Dehydrocholesterol Reductase; DHCR24,
24-Dehydrocholesterol Reductase. B. Schematic view of RORγ-mediated transcriptional
activation of target genes by endogenous sterol agonists and its inhibition by antagonists.
The circadian clock regulates RORγ expression and as a consequence the expression
of RORγ target genes. Prox1 modulates RORγ transcriptional activity. The in vivo consensus
RORE derived from ChIP-Seq analysis using liver tissue and an anti-RORγ antibody,