Development of bile acid activated receptors hybrid molecules for the treatment of inflammatory and metabolic disorders

Fiorucci, Stefano; Sepe, Valentina; Biagioli, Michele; Fiorillo, Bianca; Rapacciuolo, Pasquale; Distrutti, Eleonora; Zampella, Angela

doi:10.1016/j.bcp.2023.115776

Cited by 4 publications

(1 citation statement)

References 127 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to FXR and GPBAR1, bile acids serve as non-exclusive ligands for other nuclear receptors, including the pregnane-X-receptor (PXR) 34 , vitamin-D-receptor (VDR) 35 , peroxisome-proliferator activated receptors (PPARs) 36 , liver-X-receptors (LXRs) 37 and the retinoid orphan-related receptor (ROR) γT 38 , and membrane receptors such as the Sphingosine 1 receptor (SP1R)2 39 and M2/M3 muscarinic receptors 40,41 . In these settings, bile acids function as receptor agonists and, up to now, there is no evidence that bile acids might function as direct antagonists to any receptor.…”

Section: Introductionmentioning

confidence: 99%

Bile Acids Serve As Endogenous Antagonists Of The Leukemia Inhibitory Factor (LIF) Receptor in Oncogenesis

Di Giorgio,

Morretta,

Lupia

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

SummaryThe leukemia inhibitory factor (LIF) is member of IL-6 family of cytokines involved immune regulation, morphogenesis and oncogenesis. In cancer tissues, LIF binds a heterodimeric receptor (LIFR), formed by a LIFRβ subunit and glycoprotein(gp)130, promoting epithelial mesenchymal transition and cell growth. Bile acids are cholesterol metabolites generated at the interface of host metabolism and the intestinal microbiota. Here we demonstrated that bile acids serve as endogenous antagonist to LIFR in oncogenesis. The tissue characterization of bile acids content in non-cancer and cancer biopsy pairs from gastric adenocarcinomas (GC) demonstrated that bile acids accumulate within cancer tissues, with glyco-deoxycholic acid (GDCA) functioning as negative regulator of LIFR expression. In patient-derived organoids (hPDOs) from GC patients, GDCA reverses LIF-induced stemness and proliferation. In summary, we have identified the secondary bile acids as the first endogenous antagonist to LIFR supporting a development of bile acid-based therapies in LIF-mediated oncogenesis.

show abstract