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, is shown.