Chenodeoxycholic Acid

Primary biliary cholangitis (formerly known as primary biliary cirrhosis, PBC) is an autoimmune liver disease in which a cycle of immune mediated biliary epithelial cell injury, cholestasis and progressive fibrosis can culminate over time in an end-stage biliary cirrhosis. Both genetic and environmental influences are presumed relevant to disease initiation. PBC is most prevalent in women and those over the age of 50, but a spectrum of disease is recognised in adult patients globally; male sex, younger age at onset (1.67 × upper limit of normal and/or elevated bilirubin) should be considered for second-line therapy, of which OCA is the only currently licensed National Institute for Health and Care Excellence recommended agent. Follow-up of patients is life-long and must address treatment of the disease and management of associated symptoms.

Tauroursodeoxycholic acid (TUDCA) is a naturally occurring hydrophilic bile acid that has been used for centuries in Chinese medicine. Chemically, TUDCA is a taurine conjugate of ursodeoxycholic acid (UDCA), which in contemporary pharmacology is approved by Food and Drug Administration (FDA) for treatment of primary biliary cholangitis. Interestingly, numerous recent studies demonstrate that mechanisms of TUDCA functioning extend beyond hepatobiliary disorders. Thus, TUDCA has been demonstrated to display potential therapeutic benefits in various models of many diseases such as diabetes, obesity, and neurodegenerative diseases, mostly due to its cytoprotective effect. The mechanisms underlying this cytoprotective activity have been mainly attributed to alleviation of endoplasmic reticulum (ER) stress and stabilization of the unfolded protein response (UPR), which contributed to naming TUDCA as a chemical chaperone. Apart from that, TUDCA has also been found to reduce oxidative stress, suppress apoptosis, and decrease inflammation in many in-vitro and in-vivo models of various diseases. The latest research suggests that TUDCA can also play a role as an epigenetic modulator and act as therapeutic agent in certain types of cancer. Nevertheless, despite the massive amount of evidence demonstrating positive effects of TUDCA in pre-clinical studies, there are certain limitations restraining its wide use in patients. Here, molecular and cellular modes of action of TUDCA are described and therapeutic opportunities and limitations of this bile acid are discussed.

Accumulation of hydrophobic bile acids in the liver contributes to cholestatic liver injury. Inflammation induced by excessive bile acids is believed to play a crucial role, however, the mechanisms of bile acids triggered inflammatory response remain unclear. Recent studies have highlighted the effect of NLRP3 inflammasome in mediating liver inflammation and fibrosis. In this study, we for the first time showed that chenodeoxycholic acid (CDCA), the major hydrophobic primary bile acid involved in cholestatic liver injury, could dose-dependently induce NLRP3 inflammasome activation and secretion of pro-inflammatory cytokine-IL-1β in macrophages by promoting ROS production and K+ efflux. Mechanistically, CDCA triggered ROS formation in part through TGR5/EGFR downstream signaling, including protein kinase B, extracellular regulated protein kinases and c-Jun N-terminal kinase pathways. Meanwhile, CDCA also induced ATP release from macrophages which subsequently causes K+ efflux via P2X7 receptor. Furthermore, in vivo inhibition of NLRP3 inflammasome with caspase-1 inhibitor dramatically decreased mature IL-1β level of liver tissue and ameliorated liver fibrosis in bile duct ligation (BDL) mouse model. In conclusion, excessive CDCA may represent an endogenous danger signal to activate NLRP3 inflammasome and initiate liver inflammation during cholestasis. Our finding offers a mechanistic basis to ameliorate cholestatic liver fibrosis by targeting inflammasome activation.

Background and aimsObesity is a global health challenge significantly increasing cardiovascular disease (CVD) burden. Effective prevention and treatment necessitate targeting early pathological changes, particularly obesity-induced endothelial dysfunction (ED). This study aimed to characterize ED heterogeneity in non-hypertensive obese (NHO) individuals, investigate the association of serum metabolites with obesity-induced ED, and identify potentially predictive and therapeutic metabolites.MethodsUtilizing wire myograph, this study assessed ED of ex vivo arterioles from omental adipose tissue of 213 NHO patients, categorized into metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO). Targeted metabolomic profiling identified associations between serum metabolites and ED.ResultsObesity-induced ED in NHO patients lacked correlations with many traditional cardiovascular risk factors. The MHO and MUO individuals exhibited similar ED and metabolomic profile characteristics. Serum metabolomics identified bile acids (BAs), particularly chenodeoxycholic acid (CDCA), as negatively correlated with ED in NHO patients. Taurochenodeoxycholic acid (TCDCA), a taurine-conjugated derivative of CDCA, protected against obesity-induced ED and hypertension. Mechanistically, endothelial Farnesoid X receptor (FXR) deletion aggravated obesity-induced ED and hypertension, negating the beneficial effects of bariatric surgery or TCDCA treatment. The TCDCA-FXR activation in endothelial cells upregulated ATF4 transcription, which was suppressed by PHB1, thereby enhancing serine and one-carbon metabolism.ConclusionsThis study suggests CDCA as a promising biomarker for identification of obesity-induced ED. Taurochenodeoxycholic acid demonstrates significant therapeutic potential for alleviating various forms of obesity-induced ED. This effect is mediated by the endothelial TCDCA-FXR-PHB1-ATF4 axis, which upregulates serine and one-carbon metabolism, thereby offering a novel strategy to delay the onset of hypertension and other CVDs.