Deficiency of 3β-hydroxy-Δ(5)-C27-steroid oxidoreductase (HSD3B7), an enzyme catalyzing the second step in the pathway for bile acid synthesis, leads to a complete lack of the primary bile acids, cholic and chenodeoxycholic acids, and the accumulation of 3β,7α-dihydroxy- and 3β,7α,12α-trihydroxy-Δ(5)-cholenoic acids. Patients affected by this autosomal recessive genetic defect develop cholestatic liver disease that is clinically responsive to primary bile acid therapy. Reference standards of these compounds are needed to facilitate diagnosis and to accurately quantify biochemical responses to therapy. Described are a novel synthesis of atypical bile acids that characterize the HSD3B7 deficiency and their effect on bile acid-activated nuclear receptors, target genes and cytochromes involved in bile acid homeostasis and detoxification. The failure of 3β-hydroxy-Δ(5)-cholenoic acids to function as FXR, PXR and CAR agonists and to exert hepatoprotective actions explains the mechanism for progressive cholestatic liver disease in patients with HSD3B7 deficiency.
Keywords: 3β-Hydroxy-Δ5-C27-steroid oxidoreductase; Bile acids; Biomarkers; Diagnosis; Gene expression; Inborn errors; Mass spectrometry; Nuclear receptors; Synthesis.
Copyright © 2014 Elsevier Ltd. All rights reserved.