Tauroursodeoxycholate—Bile Acid with Chaperoning Activity: Molecular and Cellular Effects and Therapeutic Perspectives

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.

Regulation of Adipsin Expression by Endoplasmic Reticulum Stress in Adipocytes

“…A previous study reported that treatment with 4-PBA ameliorated palmitate-induced β-cell dysfunction [24]. Treatment with TUDCA also prevented β-cell dysfunction and apoptosis in diabetic mice and potentiated glucose-stimulated insulin secretion in isolated mouse pancreatic islets [25][26][27][28]. In the present study, we showed that administration of 4-PBA reduced ER stress and thereby recovered adipsin expression in adipose tissues of HFD-fed obese mice.…”

Pathological Aspects of COVID-19 as a Conformational Disease and the Use of Pharmacological Chaperones as a Potential Therapeutic Strategy

“…Several candidate pharmacological chaperones, such as tauroursodeoxycholic acid (TUDCA) and 4-phenyl butyric acid (PBA), may offer promising therapeutic avenues in this context (Chen et al, 2016). TUDCA has been most well studied, preclinically and clinically, to date (Kusaczuk, 2019). TUDCA is a taurine conjugate of ursodeoxycholic acid (UDCA), which promotes bile acid secretion and exerts a hepatocyte-protective effect.…”

“…effect of TUDCA against acute conditions such as ischemia, hypoxia, and pressure overload on the cardiovascular system have been demonstrated in various preclinical studies using cultured cells and mouse models (Kusaczuk, 2019). Chronic ER stress due to obesity induces adipose inflammation and suppresses signaling from the insulin receptor to insulin receptor substrate-1 (IRS-1), leading to insulin resistance.…”

Intrauterine exposure to low-dose DBP in the mice induces obesity in offspring via suppression of UCP1 mediated ER stress

“…Recent studies have shown that reactive protein chaperone 4-butyrate (4-PBA) and TUDCA promote protein folding in the ER and thereby maintain protein homeostasis 48,49 . Other studies have shown that chaperones can reduce leptin resistance caused by ER stress in vitro and increase leptin sensitivity in obese mice 50 .…”