Bile acids (BAs) belong to cholesterol-derived sterols. Due to the side chain carboxyl group and hydroxylation of their steroid ring they are more polar than cholesterol. They have an amphipatic character for which they are known as natural detergents. Majority of cholesterol is excreted by bile acids that are prone to enterohepatic circulation between the gallbladder and the liver. Cholesterol absorption in the intestine and cholesterol secretion into the bile both require bile salts, which are, together with enterohepatic circulation of BAs, crucial for balancing the plasma cholesterol level.
BAs are also signaling molecules. They deorphanized the farnesoid X nuclear receptor (FXR) which is now known as a ligand-inducible transcription factor responsive to BAs. It is important to note that BAs are metabolized in a similar manner as xenobiotics, contributing to the cross-talk between the endogenous and xenobiotic metabolism in the liver through nuclear receptors Pregnane X receptor (PXR), constitutive androstane receptor (CAR) and others. While their synthesis takes place exclusively in the liver, the homeostasis and excretion involve multiple organs and compartments in the body. After discovering their signaling role, BAs have been considered as pro-carcinogenic molecules. However, recent studies have provided evidence that in certain cancers, BAs can have antineoplastic features. This novel, context-dependent, dualistic finding prompted us to thoroughly assess the involvement of BAs in carcinogenesis and cancer progression.
The excess of free cholesterol is toxic to cells and needs to be excreted, primarily through conversion to more polar BAs. The introduction of a hydroxyl group in cholesterol reduces the half-life and directs the oxidized molecule to excretion. BA synthesis is thus the main cholesterol detoxification pathway where multiple cytochrome P450 (CYP) enzymes are involved in the classical or alternative pathways. The two major primary BAs in humans are cholic acid (CA) and chenodeoxycholic acid (CDCA). They are synthesized in the liver and secreted into the gallbladder as glycine or taurine conjugates. The BA composition in mice substantially differs from the humans which has to be taken into account when using mouse as a model for BA related diseases. The mouse Cyp2c70 metabolizes CDCA to more hydrophilic primary muricholic acids (MCAs).
The first enzyme of the classical BA synthesis pathway is cholesterol 7α-hydroxylase (CYP7A1), leading to 7α-cholesterol in a rate-limiting reaction step, followed by several enzymatic conversions. This enzyme is prone to the negative feedback regulation by BAs and FXR. Sterol 12α-hydroxylase (CYP8B1) lies at the branching point that leads to CA. Sterol 27-hydroxylase (CYP27A1) is needed for both CA and CDCA. In the alternative pathway, cholesterol is first metabolized by CYP27A1 to form 27-hydroxycholesterol that is a substrate for 25-hydroxycholesterol 7α-hydroxylase (CYP7B1) and later other enzymes [15]. The alternative pathway leads majorly to CDCA. The ratio of CA to CDCA is determined by the expression level of CYP8B1, which transforms a di-hydroxylated BA to tri-hydroxylated BA. The alternative pathway is estimated to account for about 10% of cholesterol conversion. Of importance, there are major differences in individual BA synthesis genes in mouse and in humans which may be due also to different biological roles of human and mouse BA species.
Among the bile acids, Lithocholic acid (LCA), Ursodeoxycholic acid (UDCA) and Chenodeoxycholic acid (CDCA) exerted antiproliferative effects in prostate cancer. Activation of Farnesoid X receptor (FXR) by CDCA inhibits proliferation of prostate cancer cells, reduces lipid anabolism via inhibiting Sterol Regulatory Element Binding Transcription Factor 1 (SREBF1) and induces the expression of the tumor suppressor phosphatase and tensin homolog (PTEN). Interestingly, FXR signaling also controls androgen metabolism in prostate cancer cells, its activation reduces the expression of UDP-glucuronosyltransferase (UGT) 2B15 and UGT2B17 within cells and causes a reduction of androgen glucuronidation. Similar to CDCA, LCA has antiproliferative effects in prostate cancer and induces apoptosis, endoplasmic reticulum stress, autophagy and mitochondrial dysfunction. UDCA induces death receptor-mediated apoptosis in human prostate cancer cells.
link.springer.com/article/1...
What is Farnesoid-X receptor (FXR)?
health.selfdecode.com/blog/...
Activation of FXR reduces plasma glucose and improves insulin sensitivity, whereas inactivation of FXR has the opposite effect.
en.wikipedia.org/wiki/Farne...
Farnesoid X Receptor Agonist / Activator:
-- Taurodeoxycholic Acid (TUDCA)
-- Ursodeoxycholic Acid (UDCA)
-- Obeticholic acid
-- Chenodeoxycholic Acid
-- Cholic Acid
-- Lithocholic Acid
-- Androsterone
-- Pregnanolone
-- Ivermectin
-- EGCG
-- Fexaramine
-- Tropifexor
-- Cafestol
-- Nidufexor
-- Tretinoin
Study: Cannabidiol Inhibits the Proliferation and Invasiveness of Prostate Cancer Cells 
