HSD3B1 links ileal steroid metabolism to bile acid regulation in patients with prostate cancer
Nikou Fotouhi, Robert Diaz, Mohammad Alyamani, Yoon-Mi Chung, Gail West, Pranab K. Mukherjee, Alireza Abdshah, Robert A. Burgess, Samreen Jatana, Rana R. McKay, Florian Rieder, Mary-Ellen Taplin, Nima Sharifi
Nikou Fotouhi, Robert Diaz, Mohammad Alyamani, Yoon-Mi Chung, Gail West, Pranab K. Mukherjee, Alireza Abdshah, Robert A. Burgess, Samreen Jatana, Rana R. McKay, Florian Rieder, Mary-Ellen Taplin, Nima Sharifi
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Research Article Endocrinology Metabolism Oncology

HSD3B1 links ileal steroid metabolism to bile acid regulation in patients with prostate cancer

Abstract

Androgen deprivation therapy (ADT), a cornerstone of advanced prostate cancer treatment, effectively suppresses androgen signaling but frequently induces systemic metabolic dysregulation. Here, we delineate an unrecognized intestinal steroid/bile acid regulatory axis that mechanistically links androgen suppression to extratumoral metabolic aberrations. HSD3B1 is the most common inherited link to prostate cancer mortality and mediates its effects by regulating steroid metabolism. Integrated metabolomic profiling of patients undergoing ADT revealed a rapid genotype-associated reduction in circulating bile acids, most pronounced in carriers of the adrenal-permissive HSD3B1 (1245C) allele. Surprisingly, analyses in human intestinal tissue and mechanistic investigations in in vitro models identified the terminal ileum as a unique site of HSD3B1 and SLC10A2 (ASBT) coexpression, where catalytically active 3βHSD1 is transcriptionally governed by liver receptor homolog-1 (LRH-1). Pharmacologic or genetic LRH-1 inhibition coordinately suppressed HSD3B1 and SLC10A2 expression and function, while inducing adaptive HSD11B2 upregulation and enhanced glucocorticoid inactivation. This LRH-1–dependent regulatory program persisted independently of androgen and glucocorticoid receptor signaling under in vitro conditions modeling androgen deprivation. These findings establish LRH-1 as a central integrator of intestinal steroidogenesis and bile acid transport and implicate the LRH-1/HSD3B1/SLC10A2 network as a mechanistic driver of ADT-associated metabolic disturbances and a potential target for therapeutic intervention.

Authors

Nikou Fotouhi, Robert Diaz, Mohammad Alyamani, Yoon-Mi Chung, Gail West, Pranab K. Mukherjee, Alireza Abdshah, Robert A. Burgess, Samreen Jatana, Rana R. McKay, Florian Rieder, Mary-Ellen Taplin, Nima Sharifi

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Figure 6

Integrated mechanistic model of intestinal bile acid regulation through the LRH-1/3βHSD1/SLC10A2 axis during ADT.

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Integrated mechanistic model of intestinal bile acid regulation through ...
(A and B) Schematic summarizing experimental findings. Under physiologic androgen-replete conditions, LRH-1 sustains HSD3B1 and SLC10A2 expression in terminal ileal enterocytes, supporting efficient bile acid uptake and recycling. LRH-1 also maintains local GR expression, and under androgen-replete conditions, GR signaling contributes to SLC10A2 regulation. During androgen-deprived conditions, adrenal-permissive (HSD3B1 1245C) alleles encode a more stable 3βHSD1 enzyme that efficiently converts DHEA to downstream androgens, reducing dependence on LRH-1–driven HSD3B1 transcription and thereby attenuating LRH-1 activity, including expression of downstream targets such as SLC10A2. In contrast, adrenal-restrictive (HSD3B1 1245A) alleles encode a less stable enzyme, maintaining reliance on LRH-1–mediated HSD3B1 induction, which in turn modestly induces SLC10A2 and other LRH-1 targets. In this context, LRH-1 remains the predominant regulator of the HSD3B1/SLC10A2 axis, while GR signaling becomes functionally uncoupled from SLC10A2 control. Reduced LRH-1 activity induces HSD11B2 and local cortisol inactivation, further reinforcing the insulation of this pathway from canonical glucocorticoid signaling. Together, this model integrates genetic and therapeutic contexts to illustrate an intestinal steroid/bile acid loop during ADT. T, testosterone.