Abstract
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.
Highlights
Traditional Chinese medicine has valued animal bile for its use in pharmacological and clinical applications
AktSer473 in muscle, without causing such alterations in adipose tissue. These results suggest that endoplasmic reticulum (ER) stress-mitigating activity of Tauroursodeoxycholic acid (TUDCA) has been widely demonstrated in in-vitro and animal model studies of diabetes and obesity, research conducted on humans may not fully confirm these findings
A marked reduction in Aβ1-40 and Aβ1-42 levels was noticed in both the frontal cortex and hippocampus of TUDCA-fed amyloid precursor protein (APP)/PS1 mice, suggesting that TUDCA might interfere with Aβ formation possibly via regulation of lipid-metabolism mediators connected with APP processing [124,125]. These results suggest that TUDCA supplementation might be considered as a potential therapeutic strategy for the prevention and treatment of Alzheimer’s disease
Summary
Traditional Chinese medicine has valued animal bile for its use in pharmacological and clinical applications. In most cases they present rather low toxicity to the organism and are able to cross the blood-brain barrier [4] These favorable characteristics of TUDCA are the main reason why it has been studied as a potential therapeutic agent in a broad spectrum of diseases. 7α-hydroxycholesterol is converted to 7α-hydroxy-4-cholestene-3-one by 3β-hydroxy-∆5-C27-steroid dehydroxylase (3β-HSD, HSD3B7) This is followed by the series of reactions including steroid side chain cleavage catalyzed by the mitochondrial sterol 27-hydroxylase (CYP27A1) to form chenodeoxycholic acid [4]. TUDCA/UDCA has been shown to interfere with E2F-1/Mdm-2/p53 apoptotic pathway [32,33,34,35] and to promote dissociation of heat shock protein 90 (HSP90) from mineralocorticoid receptor (MR) and GR, resulting in subsequent nuclear translocation of bile acid-receptor complex and reduction of apoptosis [36,37]. This review is focused on demonstrating molecular and cellular effects of TUDCA in hepatobiliary and ER stress-related disorders and tries to highlight its therapeutic potential and certain limitations restraining its use as an effective therapeutic agent in a broad spectrum of diseases
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