Non-Alcoholic Fatty Liver Disease: The Effect of Bile Acids and Farnesoid X Receptor
Agonists on Pathophysiology and Treatment
Bile acids produced in the liver as an end product of cholesterol catabolism were
originally categorised as physiological detergents that facilitated the metabolism of dietary
lipids and lipid soluble vitamins, and the hepatobiliary secretion of endogenous
metabolites and xenobiotics.
However, recent interest in bile acids over the past few
years has shed new light on their roles in both the synthetic
and regulatory metabolic pathways,
pertaining to lipid, carbohydrate and cholesterol
regulation acting as indispensable signalling
molecules co-ordinating these network of biological processes.
Whilst bile acids (Chenodexoycholic acid (CDCA)cid (DCA), Lithocholic acid (LCA),
Cholic Acid (CA)) can negatively feedback their own production,
they can also act as endogenous ligands for nuclear receptors to facilitate this regulation.
The nuclear receptor, Farnesoid X Receptor (FXR; NR1H4) was thceptor discovered,8
followed by other nuclear receptors in the NR1I subfamily, namely Constitutive Androstane
Receptor (CAR; NR1I3), Pregnane X Receptor (PXR; NR1I2) and Vitamin D Receptor (VDR;
NR1I1).
In terms of nuclear receptor activation, PXR and
VDR are stimulated by lithocholic acid (EC50 of approximately 100 nM), which is a hydrophobic bile acid derived from the 7-dehydroxylation of CDCA by intestinal bacteria.2,4 FXR
though can be stimulated to varying degrees by most bile acids (CDCA>LCA=DCA>CA),
but with the highest potency by
CDCA, with an EC50 of approximately 10 µM.2
Conversely,
constitutive androstane receptor is not triggered directly by bile
acids but nonetheless is vital for controlling detoxification and
transport of bile acids. Of all the nuclear receptors, VDR is
expressed broadly across different tissue types. However, FXR
and PXR are found abundantly, mainly in tissues in direct
contact with bile acids for example in the intestine and liver.
Liver Res Open J. 2015; 1(2): 32-40. doi: 10.17140/LROJ-1-106
