TUDCA Ameliorates Liver Injury Via Activation of SIRT1–FXR Signaling in a Rat Hemorrhagic Shock Model

Abstract

Objective: The aim of this study was to investigate the changes of bile acids in the liver during hemorrhagic shock (HS) and their potential to attenuate liver injury via activation of SIRT1 (sirtuin 1)–FXR (farnesoid X receptor) signaling. Methods: A Sprague–Dawley (SD) rat HS model was established, whereas HepG2 cells were hypoxically cultured to simulate HS in vitro. Liver bile acids (BA) were profiled with ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). FXR expression was detected by western blot and immunohistochemistry. The mRNA levels of SIRT1 and FXR were detected by polymerase chain reaction. Protein expression of SIRT1, FoxM1, NF-κB, acetyl-NF-κB, p53, and acetyl-p53 was analyzed by western blot. Hepatocyte apoptosis and proliferation were measured by TUNEL assay and Ki-67 staining, respectively. Serum and supernatant cytokines were analyzed using ELISA assays. Liver injury was also assessed. To investigate the possible mechanisms, SIRT1 agonist (SRT1720), SIRT1 inhibitor (EX527), and FXR inhibitor (Z-guggulsterone) were used. Results: Tauroursodeoxycholic acid (TUDCA) in the liver decreased significantly after HS. SIRT1 and FXR expression was time-dependently downregulated by HS or hypoxia condition. TUDCA upregulated SIRT1–FXR activity, which inhibited expression and acetylation of NF-κB and p53 and increased FoxM1 expression, leading to decreased inflammatory response and apoptosis and increased proliferative capacity in hepatocytes, and attenuation of liver injury. EX527 pretreatment reversed the protective effect of TUDCA. Moreover, Z-guggulsterone supplementation decreased the protective effect of TUDCA in vitro. Conclusion: TUDCA in the liver decreased during HS. TUDCA supplementation might attenuate HS-induced liver injury by upregulating SIRT1–FXR signaling.

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

“…TUDCA/UDCA has been used in Chinese medicine for centuries, and hundreds of studies have already underscored its beneficial effects in the treatment of many pathological conditions. Nevertheless, TUDCA is constantly a very intriguing pharmacological agent and a growing number of pre-clinical and clinical research is still performed, unraveling novel aspects of TUDCA functioning [94,[182][183][184][185][186][187]. Although through the years this bile acid has been demonstrated to be a very efficient hepatoprotectant and ER stress alleviator, many innovative contemporary reports inform about its novel potential applications and molecular modes of action.…”

“…Interestingly, TUDCA-dependent inhibition of class I and II HDAC enzymes restored the expression GLUT4, resulting in improvement of insulin sensitivity and glucose tolerance [189]. Moreover, TUDCA has been found to modify the expression of sirtuins, which are NAD-dependent deacetylases responsible for removing acetyl groups from many histone and non-histone proteins [185,190]. Thus, TUDCA decreased ethanol-induced overexpression of sirtuin-2 [190] and restored hypoxia-and hemorrhagic shock-induced down-regulation of sirtuin-1 [185].…”

“…Moreover, TUDCA has been found to modify the expression of sirtuins, which are NAD-dependent deacetylases responsible for removing acetyl groups from many histone and non-histone proteins [185,190]. Thus, TUDCA decreased ethanol-induced overexpression of sirtuin-2 [190] and restored hypoxia-and hemorrhagic shock-induced down-regulation of sirtuin-1 [185]. It is commonly known that modulation of the epigenetic environment of the cell may interfere with a plethora of distinct cellular processes such as apoptosis, cell cycle, differentiation, or senescence, and also may affect the regulation of many metabolic pathways [191,192].…”

The Specific Bile Acid Profile of Shock: A Hypothesis Generating Appraisal of the Literature

“…This general increase disqualifies the total amount of bile acids in serum as a biomarker to differentiate between disease states but might suit to estimate a liver involvement early on. However, it clearly shows that the liver and especially the bile are affected in all critically ill patients at a rather early point during the course of the disease, a finding that has been described before [22]. This finding is in strong contrast to perceived regular clinical practice where secondary liver injury is a late, often additionally found, and frequently final disease state following a (long) course of critical illness.…”

Baicalin Protects Against 17α-Ethinylestradiol-Induced Cholestasis via the Sirtuin 1/Hepatic Nuclear Receptor-1α/Farnesoid X Receptor Pathway

“…It has previously been reported that activation of Sirt1 decreased the production of several pro-inflammatory cytokines, including TNF-a, IL-12, and IL-18 in EIC rats and protected syncytiotrophoblasts against TCA-induced inflammatory injury through the Sirt1-NF-kB signaling pathway (Liao et al, 2018). Moreover, NF-kB is a downstream gene of FXR, and upregulating Sirt1/FXR/NF-kB signaling had an efficient protective effect on rats from hemorrhagic shock induced liver injury by decreasing inflammatory responses (Zhang et al, 2017;Sun et al, 2019;Yu et al, 2019). Thus, we hypothesized that activation of FXR by baicalin through the Sirt1/HNF-1a signaling pathway might also play a key role in regulating the NF-kB pathway, which would need to be further investigated.…”