UDCA, NorUDCA, and TUDCA in Liver Diseases: A Review of Their Mechanisms of Action and Clinical Applications

[madman]

Abstract

Bile acids (BAs) are key molecules in generating bile flow, which is an essential function of the liver. In the last decades, there have been great advances in the understanding of BA physiology, and new insights have emerged regarding the role of BAs in determining cell damage and death in several liver diseases. This new knowledge has helped to better delineate the pathophysiology of cholestasis and the adaptive responses of hepatocytes to cholestatic liver injury as well as of the mechanisms of injury of biliary epithelia. In this context, therapeutic approaches for liver diseases using hydrophilic BA (i.e., ursodeoxycholic acid, tauroursodeoxycholic, and, more recently, norursodeoxycholic acid), have been revamped. In the present review, we summarize current experimental and clinical data regarding these BAs and its role in the treatment of certain liver diseases.


















5 Summary and Outlook

Significant advances have been made in the understanding of the beneficial effects of hydrophilic BA in the liver. Both basic science and clinical studies have either disclosed the mechanisms of action or proved the efficacy of compounds that were found to be medically useful hundreds of years ago. The science of BA will continue developing, and new evidence will likely provide foundations for new, evidence based, and effective treatments for certain common and uncommon liver diseases

 

[madman]

 

[madman]

Fig. 2 Overview of the main hepatoprotective mechanisms of action of UDCA and TUDCA. In cholestasis, hydrophobic bile acids induce many cellular changes that can be counteracted by hydrophilic bile acids such as UDCA and TUDCA. (1) Hydrophobic bile acids are strong detergents that can cause membrane disruption by lipid solubilization, while hydrophilic bile acids like UDCA can bind to the apolar domain of cell membranes, stabilizing its molecular structure. (2) Bicarbonate secretion by hepatocytes and cholangiocytes has protective action against the detergent effects of hydrophobic bile acids. Treatment with hydrophilic bile acids induces bicarbonate secretion by several mechanisms including increasing of the anion exchanger 2 [AE2] expression. AE2 exchanges chloride by bicarbonate in both hepatocytes and cholangiocytes. (3) Hydrophilic bile acids can also inhibit apoptotic signaling pathways at the level of mitochondria or indirectly through anti-inflammatory effects by binding the glucocorticoid receptor (GR) and counteracting the pro-inflammatory effects of bile acids, which are mediated by toll-like receptor 9 (TLR9). (4) Cholestasis induces endocytic internalization of canalicular transporters, like the bile salt export pump (BSEP) and the multidrug resistance-associated protein 2 (MRP2). Treatment with hydrophilic bile acids increases the translocation of transporters such as BSEP and MRP2 into the canalicular membrane.

 

[madman]

Fig.3 The biliary HCO3 umbrella hypothesis and the hepatoprotective actions of TUDCA, UDCA, and NorUDCA. Hydrophobic bile acids are toxic to cholangiocytes, inducing senescence, endoplasmic reticulum stress, autophagy, and cell death. These effects are counteracted by bicarbonate secretion via the Cl/HCO3anion exchanger 2 [AE2] in hepatocytes and cholangiocytes and likely also by transmembrane member 16A (TMEM16A) in cholangiocytes. UDCA, TUDCA, and NorUDCA have been observed to have protective effects in the liver by preventing bicarbonate depletion on the apical side of cholangiocytes, thus exercising cytoprotective effects. Particularly, NorUDCA, due to its resistance to amidation, can undergo cholehepatic shunting and potently promote bicarbonate secretion into the bile duct. Although most of the UDCA is secreted as a glycine conjugate in humans, taurine conjugation predominates in rodents. Secretion of TUDCA is mediated by the canalicular bile salt export pump (BSEP).

 

[madman]