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Basic Science Aspects

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

Sun, Silei; Zhao, Bing; Qi, Mengzhi; Yao, Yi; Xu, Lili; Ji, Ran; Chen, Weiwei; Wang, Jinlong; Huang, Shunwei; Ma, Li; Chen, Ying; Yang, Zhitao; Sheng, Huiqiu; Fei, Jian§; Chen, Erzhen; Mao, Enqiang

Author Information
doi: 10.1097/SHK.0000000000001351

Abstract

INTRODUCTION

Hemorrhagic shock (HS) is a life-threatening condition, which requires immediate intervention. It is estimated that HS results in 1.9 million deaths per year worldwide (1). This condition is characterized by hypoperfusion followed by tissue hypoxia, leading to oxidative stress and inflammation (2). At the cellular level, insufficient oxygen supply results in a failure to meet the oxygen demand of aerobic metabolism, resulting in cell death, such as necrosis and apoptosis (3). As a result, HS is frequently associated with systemic inflammatory response syndrome and end organ damage.

Hepatic dysfunction is a common result of HS; if not treated effectively, it might progress to liver failure, and even further develop into multiple organ dysfunction syndrome, which leads to a poor prognosis. Although many attempts have been made to develop a suitable treatment for this condition, such as remote ischemic conditioning (4), no ideal treatment has yet been found (5). Against this background, the mechanism of hepatic dysfunction during HS needs to be elucidated to develop new therapeutic strategies.

Bile acids (BA) are synthesized in the liver and function by binding to their receptors FXR and Takeda G-protein-coupled receptor 5 (TGR5) (6). FXR, highly expressed in liver and intestine, plays crucial roles in maintaining BA homeostasis, lipoprotein metabolism, hepatic regeneration, and inflammation (7–9). A recent study indicated the therapeutic potential of FXR for ischemia–reperfusion injury (10). SIRT1 belongs to the sirtuin family, which consists of highly conserved mammalian proteins involved in cellular energy homeostasis (11). Studies have suggested that the reduction of hepatic SIRT1 in mice leads to impaired BA homeostasis, increased apoptosis, inhibition of hepatocyte proliferation, and worsening of hepatic steatosis and inflammation (12, 13). In addition, SIRT1 has been shown to modulate the activation of FXR and deletion of hepatic SIRT1 decreases FXR signaling (14). Furthermore, activation of SIRT1 protects various organs from ischemia–reperfusion injury (15, 16). A recent study showed that bile acids might modulate SIRT1 expression in liver cholestasis and regeneration (17, 18). Our previous studies indicated that biliary tract external drainage alleviated multiple organ injury induced by HS (19, 20); however, it failed to improve or even aggravated liver damage. We speculated that BAs, as the main components in bile, might have protective effects on liver function.

In this study, we hypothesized that, as protective BA decreased during HS, BA supplementation might protect liver function via the activation of SIRT1–FXR signaling. To test this hypothesis, we first used an established rat model of HS. BAs in HS rat liver were profiled with UPLC-MS/MS and “reduced BAs” were identified. Next, we investigate whether the administration of these “reduced BAs” might protect against HS-induced liver injury. We also studied the possible mechanisms behind BA protection of liver function in HS.

MATERIALS AND METHODS

Animals

Male Sprague–Dawley (SD) rats (275–325 g; Shanghai Laboratory Animal Center of the Chinese Academy of Sciences) were housed and fed under specific pathogen-free conditions. The animals were acclimatized to laboratory conditions (25°C, 12 h/12 h light/dark cycle, 50% humidity, with free access to food and water) for one week before the start of the study. The rats were fasted overnight before surgery with free access to water. The experiment was carried out in accordance with the guidelines for the care and use of laboratory animals established by the Animal Use and Care Committee of Shanghai Committee on Animal Care. All surgical procedures were approved by the Institutional Animal Care and Use Committee (IACUC) at Shanghai Jiao Tong University (Shanghai, China).

Hemorrhagic shock model

The HS model was established as described previously (21), with a few modifications. In brief, after the rats had been anesthetized (i.p., sodium pentobarbital at 50 mg/kg), the right femoral artery was dissected aseptically and then catheterized with a heparinized polyethylene tube for blood pressure monitoring. Afterwards, the left femoral artery was catheterized with the same technique and a heparinized syringe was attached at the end for blood collection. The HS was initiated by withdrawing blood until the mean arterial pressure (MAP) decreased to 30 ± 5 mmHg and was maintained for 1 h by withdrawing or reinfusing blood. Resuscitation was performed through the left femoral artery within 30 min by reinfusing all lost blood with the same volume of Ringer's solution. Sham rats underwent pentobarbital anesthesia, laparotomy, vascular cannulation, and suturing, but no blood withdrawal. SRT1720 (20 mg/kg, i.v.; MCE, Monmouth Junction, NJ) or TUDCA (50 mg/kg, 100 mg/kg, or 150 mg/kg, i.p.) was given during the resuscitation stage with Ringer's solution. EX527 (10 mg/kg, i.p.; MCE) was administered 30 min before operation. Rats were euthanized by decapitation at 6, 12, and 24 h after resuscitation. Serum and liver samples were collected, flash-frozen, and stored at −80°C before analysis.

UPLC-MS/MS

The liver samples were homogenized, and the total BAs in the liver were extracted with chloroform and methanol for detection. The UPLC-MS/MS analysis was performed on a Waters Acquity UPLC system (Waters, Milford, Mass) coupled to a Triple Quad 5500 tandem mass spectrometer (AB Sciex, Framingham, Mass).

Cell culture experiments

HepG2 cells (purchased from Stem Cell Bank, Chinese Academy of Sciences) were cultured in Dulbecco's modified Eagle's medium (DMEM) with 10% fetal bovine serum and 1% penicillin–streptomycin. Hypoxic conditions (1% O2, 5% CO2, 94% N2) were applied to simulate HS. Cells were cultured under hypoxia for 24 h and treated with SRT1720 (10 nM) or TUDCA (10 μM, 20 μM, 30 μM) for the last 6 h. For FXR inhibition, Z-guggulsterone (30 μM, FXR inhibitor; Santa Cruz Biotechnology, Santa Cruz, Calif) was added 8 h before treatment with TUDCA. Cells were collected for protein extraction or prepared for subsequent assays.

Cell viability assay

Cell viability was assessed with the Cell Counting Kit-8 (CCK-8; Beyotime, Guangzhou, Guangdong, China) following the manufacturer's instructions. In brief, cells were seeded at 3 × 105 cells per well into 96-well plates in triplicate. Then, 10 μL of CCK-8 solution was added to the cells in each well after the treatment with TUDCA at the indicated concentrations, and then incubated at 37°C for 3 h. Absorbance of the culture medium was detected at 450 nm on a microplate reader (Lab systems, Vantaa, Finland).

Enzyme-linked immunosorbent assay

Serum IL-1β, IL-6, IL-10, and TNF-α levels were quantified using enzyme-linked immunosorbent assay (ELISA) kits in accordance with the manufacturer's instructions (Bio-Rad, Berkeley, Calif). The concentrations were calculated using a standard curve.

Histological examination

After fixation in 4% paraformaldehyde for 24 h, liver samples were subjected to hematoxylin and eosin (H&E) staining. The slides were examined under an optical microscope by two independent pathologists in a blinded fashion. Six fields per section were evaluated under 200 × magnification. The severity of liver injury observed in tissue sections was scored as follows: 0, minimal or no evidence of injury; 1, mild injury consisting of cytoplasmic vacuolation and focal nuclear pyknosis; 2, moderate-to-severe injury with extensive nuclear pyknosis, cytoplasmic hypereosinophilia, and loss of intercellular borders; and 3, severe necrosis with disintegration of hepatic cords, hemorrhage, and neutrophil infiltration (22).

Immunohistochemistry

Paraffin-embedded liver sections were stained with Ki-67 or FXR antibody. The 5-μm sections were pretreated using heat-mediated antigen retrieval with sodium citrate buffer (pH 6) for 20 min, and then washed twice with TBST [tris-buffered saline (TBS) with 0.025% Triton X-100] for 5 min. Blocking was performed in TBS buffer with 10% nonimmune goat serum and 1% bovine serum albumin to eliminate nonspecific staining. After blocking, the sections were incubated overnight at 4°C with an optimally diluted rabbit polyclonal anti-rat Ki-67 antibody (1:200; Abcam, Cambridge Science Park, Cambridge, UK) or anti-FXR antibody (1:200; Invitrogen, Carlsbad, Calif). The sections were washed with phosphate-buffered saline (PBS), and incubated with a goat anti-rabbit biotinylated secondary antibody for 30 min, and visualized using a horseradish peroxidase (HRP)-conjugated avidin–biotin–peroxidase technique (ABC) system with 3,3-N-diaminobenzidine tetrahydrochloride (DAB) as the chromogen. The sections were then counterstained with hematoxylin and mounted with p-xylene-bis-pyridinium bromide (DPX) for microscopic examination. The experimental results were analyzed by Image J software. For analysis of the results of FXR expression, sum the optical density values of the positive parts of all hepatocytes nuclei, and then divide by the sum of the areas of all nuclei. For analysis of the expression of Ki-67, count the percentage of positive cells.

Quantitative real-time PCR

Total RNA was extracted from frozen liver tissues or HepG2 cells and reverse-transcribed into cDNA with a PrimeScript RT Master Mix Kit following the manufacturer's instructions (Takara, Kusatsu, Shiga, Japan), Quantitative real-time PCR was performed using an SYBR Premix Ex Taq II Kit (Takara) to determine the expression levels of target genes, and the results were normalized against β-actin expression. Amplification was performed in a Step One Real-Time PCR system (Applied Biosystems, Grand Island, NY). The following primers were used in this study: rat β-actin (5′-TCAGGTCATCACTATCGGCAAT-3′ and 5′-AAAGAAAGGGTGTAAAACGCA-3′), rat SIRT1 (5′-GCTCGCCTTGCTGTGGACTTC-3′ and 5′-GTGACACAGAGATGGCTGGAACTG-3′), rat FXR (5′-CGTCGGAAGTGCCAGGATTGC-3′ and 5′-CCTTCGCTGTCCTCATTCACTGTC-3′), human β-actin (5′-CTCCATCCTGGCCTCGCTGT-3′ and 5′-GCTGTCACCTTCACCGTTCC-3′), human SIRT1 (5′-TATACCCAGAACATAGACACGC-3′ and 5′-CTCTGGTTTCATGATAGCAAGC-3′), and human FXR (5′-TACCAAAAACGCTGTGTACAAG-3′ and 5′-TTCCTTAGTCGACACTCTTGAC-3′).

TUNEL assay

DNA fragmentation in liver sections was assessed using the TUNEL assay (Cell Death Detection Kit; Roche, Mannheim, Germany). Briefly, air-dried slides were fixed with 4% paraformaldehyde for 30 min at room temperature (RT), washed 3 times with PBS for 10 min, and then permeabilized with 1% Triton X-100 for 4 min at 4°C. Then, the TdT-labeled nucleotide mix was added to each slide and incubated at 37°C for 60 min in the dark. The slides were washed twice with PBS and then counterstained with 10 mg/mL 4,6-diamidino-2-phenylindole (DAPI) for 5 min at 37°C.

Western blot analysis

Liver tissues from all animals were frozen immediately in liquid nitrogen and then stored at −80°C for western blot analysis. Briefly, samples were homogenized in RIPA lysis buffer (Beyotime) for 1 h at 4°C and total protein was extracted by centrifugation (12,000 rpm, 10 min, 4°C). Protein concentration was determined using a BCA Protein Assay Kit (Beyotime). Proteins were separated using SDS–polyacrylamide gel electrophoresis (PAGE) and transferred to polyvinylidene difluoride (PVDF) membranes. TBST containing 5% skimmed milk powder was used for blocking membranes at RT for 1 h. Next, the membranes were incubated with primary antibodies overnight at 4°C. Primary antibodies were a mouse monoclonal anti-SIRT1 (1:8,000; Abcam, Cambridge, UK), a mouse monoclonal anti-FXR (1:1,000; Invitrogen), a rabbit polyclonal anti-FOXM-1 (1:1,000, Abcam), anti-NF-kB p65 (1:1,000; Abcam), anti-NF-kB p65 (acetyl K310) (1:1,000; Abcam), anti-p53 antibody (1:1,000; Abcam), anti-acetyl-p53 (acetyl K305) (1:1,000; Abcam), and a mouse monoclonal anti-β-actin (1:1,000; Beyotime). The blots were incubated with an HRP-conjugated secondary antibody for 1 h at RT and reacted with an enhanced chemiluminescence substrate (Millipore). The resulting chemiluminescence was recorded using an imaging system (Imagequant LAS 400; GE Healthcare, Pittsburgh, Pa). The enhanced chemiluminescence signals were digitized using Adobe Photoshop CC software to quantify the protein expression levels. Relative protein expression was normalized to β-actin, and the results are expressed as fold change relative to the baseline levels in each group.

Statistical analysis

The measured data are expressed as the mean ± standard deviation (SD). The significance of differences between different groups was determined via the unpaired Student t test and one-way ANOVA followed by Tukey's post hoc test. P < 0.05 was considered statistically significant. All data were analyzed using GraphPad Prism 6.0.

RESULTS

SIRT1 and FXR expression was downregulated in HS rat liver or HepG2 cultured under hypoxic conditions

The expression levels of SIRT1 and FXR proteins were detected in the liver of rats with HS. FXR expression was also immunohistochemically detected. The results indicated that the expression of both SIRT1 and FXR proteins was downregulated, in a time-dependent manner (P < 0.05) (Fig. 1, A–C, G; Fig. S1, https://links.lww.com/SHK/A867). We next cultured HepG2 cells under hypoxic conditions, the results showed that hypoxia led to decreased expression of SIRT1 and FXR in these cells (P < 0.05) (Fig. 1, D–F). Our study indicates that HS or hypoxia decreased the expression of SIRT1 and FXR.

F1
Fig. 1:
HS and hypoxic conditions decreased the expression of SIRT1 and FXR in rat liver and HepG2, respectively.

The composition of BAs changed significantly in the liver of rats with HS

The concentration of BAs in the liver was quantified with UPLC-MS/MS. The results indicated that deoxycholic acid (DCA) concentration decreased at 24 h after HS. The concentrations of taurine-conjugated cholic acid (TCA) and taurine-conjugated (alpha + beta) muricholic acid (T (α + β) MCA) decreased at 12 h after HS. The concentration of TUDCA has been decreased with increasing time after HS (Fig. 2).

F2
Fig. 2:
Bile acid changes under HS.

To investigate the influence of TUDCA on the cell viability of HepG2 cells, TUDCA was added to these cells, the results indicated that the survival rate of HepG2 was more than 95%, but decreased slightly as the concentration of TUDCA increased from 5 to 20 μM. The survival rate decreased to less than 90% when TUDCA concentration exceeded 30 μM (Fig. 3).

F3
Fig. 3:
Cell viability assay.

TUDCA increased the expression of SIRT1 and FXR both in vivo and in vitro

To investigate whether TUDCA could protect the hepatic function, it was given to the HS rats during the resuscitation stage and to the HepG2 during hypoxic culture. SRT1720 was also administered as a positive control. Western blot and PCR results indicated that TUDCA upregulated the mRNA levels and protein expression of SIRT1 and FXR (P < 0.05) (Fig. 4). However, as the results indicated, with the increase of TUDCA concentration, the expression of FXR in the liver of HS rats or HepG2 cultured under hypoxic condition decreased.

F4
Fig. 4:
TUDCA enhanced the expression of SIRT1 and FXR both in vivo and in vitro.

TUDCA attenuated liver injury in rats with HS

Histologic assessment of the liver upon HE staining revealed clear pathological changes, including necrosis, extensive nuclear pyknosis, cytoplasmic hypereosinophilia, loss of intercellular borders, hemorrhage, and neutrophil infiltration, in the HS-treated rats. This was significantly improved with the administration of TUDCA (Fig. 5, A and D). Biochemical markers of liver injury showed the same trend. Specifically, treatment with TUDCA significantly decreased serum ALT and AST levels in HS-treated rats, further documenting its protective role against liver injury in the HS model (Fig. 6, A and B).

F5
Fig. 5:
TUDCA attenuated HS induced liver injury histologically, restored hepatocyte proliferation and inhibited hepatocyte apoptosis.
F6
Fig. 6:
TUDCA decreased the levels of serum transaminases and cytokines.

TUDCA reduced hepatocyte apoptosis and restored hepatocyte proliferation in HS-treated rats

Apoptosis is a common form of cell death occurring after cell damage. Liver regeneration plays a vital role in hepatic repair after liver damage. The results in this study indicated numerous TUNEL-positive cells seen in the HS group compared with the level in the Sham group. Treatment with TUDCA significantly decreased TUNEL-positive cells (Fig. 5, C and F). Hepatocyte proliferation was significantly decreased in the HS-treated rats, as indicated by Ki-67 staining, whereas treatment with TUDCA restored hepatocyte proliferation under HS (Fig. 5, B and E).

TUDCA reduced inflammation in the rat model of HS

Serum cytokines were analyzed to assess the systemic inflammatory response. The results showed that serum levels of IL-1β, IL-6, IL-10, and TNF-α significantly increased after HS. Their levels were profoundly decreased with TUDCA treatment (Fig. 6, D–F).

TUDCA attenuated liver injury by modulating the SIRT1–FXR pathway and its downstream signaling

To investigate the underlying mechanisms by which TUDCA improved liver injury in rats with HS, we analyzed the activity of the SIRT1FXR pathway and its downstream signaling, including NF-κB, p53, and FoxM1. Our results revealed that SIRT1 and FXR were significantly upregulated compared with the levels in the HS group, which was accompanied by decreased expression and acetylation of NF-κB and p53, along with increased expression of FoxM1 (Fig. 7). The administration of EX527 inhibited the expression of SIRT1 and FXR, reversed its downstream signaling, and reduced the protective effect of TUDCA (Figs. 6 and 7).

F7
Fig. 7:
TUDCA modulated NF-κB, p53, and FoxM1 signaling via upregulating the expression of SIRT1 and FXR in the liver of rats with HS.

We further explored whether SIRT1 regulates NF-κB, p53, and FoxM1 via the activation of FXR in vitro using HepG2 cells. The results indicated that hypoxic conditions downregulated the expression of SIRT1 and FXR in HepG2, and modulated downstream signaling. Treatment with TUDCA increased the expression of SIRT1 and FXR, which decreased the expression and acetylation of NF-κB and p53 while increasing the expression of FoxM1, exhibiting a protective effect. The inhibition of FXR by Z-guggulstrone did not affect the acetylation of NF-κB and p53, but increased the expression of both, thereby impairing the protective effect of TUDCA (Figs. 8 and 9). These findings indicate that TUDCA modulated the expression and acetylation of NF-κB and p53 and the expression of FoxM1 by upregulating SIRT1–FXR signaling.

F8
Fig. 8:
TUDCA modulated NF-κB, p53, and FoxM1 signaling via upregulating SIRT1–FXR signaling in HepG2 under hypoxic conditions.
F9
Fig. 9:
TUDCA attenuated inflammation and apoptosis in HepG2 under hypoxic conditions.

DISCUSSION

HS due to trauma remains the leading cause of morbidity and mortality worldwide (23). Liver is considered to be the most frequently affected organ after HS. It is estimated that 20% of patients in hypovolemic shock exhibit liver dysfunction (24). Despite an increased understanding of the mechanisms behind HS-induced hepatic injury, the treatment remains limited to preventive and supportive care. In this study, we found that TUDCA in the liver decreased following HS. In addition, HS led to decreased expression of SIRT1 and FXR in rat liver and human HepG2 cells. TUDCA supplementation enhanced the expression of SIRT1 and FXR, which downregulated the expression and acetylation of NF-κB and p53, and increased the expression of FoxM1, exhibiting a protective effect on liver function. Furthermore, the inhibition of SIRT1 or FXR attenuated the protective effect of TUDCA.

TUDCA is the taurine-conjugated form of ursodeoxycholic acid (UDCA); it has been shown to reduce inflammation and apoptosis in ischemia–reperfusion animal models (25). In addition, studies have indicated that TUDCA exhibits protective effects by inhibiting endoplasmic reticulum stress in rat models of several diseases (26, 27). These findings indicate that TUDCA might be beneficial for liver function under HS. Our results of BA profiling with UPLC-MS/MS demonstrated that the concentration of TUDCA in the liver decreased significantly after HS. Furthermore, intraperitoneal supplementation of TUDCA attenuated liver histological injury, decreased levels of serum transaminase and cytokines, inhibited apoptosis, and restored hepatocyte proliferation.

Despite substantial efforts, the current options for treating liver dysfunction in clinical practice are still limited. The underlying cause of this difficulty is the complex mechanism involved in HS-induced liver damage.

HS leads to the activation of Kupffer cells in the liver, causing increased secretion of inflammatory cytokines, which could affect multiple organs via blood and bile circulation (20). Apoptosis is also common in liver cell damage after shock (28), but interventions focusing on apoptosis failed to improve liver function (29). Moreover, studies focusing on the stimulation of pathways involved in liver regeneration have shown that it can protect the liver from ischemia–reperfusion injury (30). Therefore, we speculated that simultaneous interventions in hepatocyte inflammatory response, apoptosis, and proliferation might be a worthwhile approach to treat HS-induced liver injury.

SIRT1, the mammalian homolog of yeast Sir2, is an NAD-dependent protein deacetylase. It is involved in a wide range of cellular processes, including aging, stress response, inflammation, metabolism, cell proliferation, and apoptosis (31). It has been reported that the activation of SIRT1 inhibited inflammation and apoptosis through the regulation of FXR and its downstream signaling in a cholestatic liver injury model (32). Our studies demonstrated that HS decreased the expression of SIRT1, downregulating the expression of FXR, which is in consistent with previous research documenting that SIRT1 regulates the expression of FXR (14). FXR, as a BA receptor, has been shown to regulate inflammation through inhibition of the NLRP3 inflammasome in a sepsis model of mice (33). In addition, FXR plays an important role in the regeneration and repair after liver injury (34). Our results indicate that the administration of TUDCA significantly upregulated the activity of SIRT1–FXR signaling, which exhibited a protective effect on HS-induced liver injury by modulating downstream signaling involved in hepatocyte inflammation, apoptosis, and proliferation.

In this study, we first detected the reduction of TUDCA in rat liver under HS conditions, and then investigated its protective effect on liver function and the potential mechanisms involved. This provided a theoretical basis for the application of TUDCA in hepatic dysfunction caused by HS.

However, changes in bile acids in the enterohepatic circulation during shock are complex, and their interaction with the gut microbiota may affect the liver and other organs. In this study, we combined the findings from reports of other researchers and our preliminary results of BA profiling to specifically study the effects of TUDCA on liver function, which may have certain limitations. In addition, our results showed that the expression of FXR decreased with the increase of TUDCA concentration, which indicated that TUDCA might have a dose-dependent biphasic effect on FXR expression via unknown mechanisms. Further research is needed to elucidate the mechanism behind this phenomenon and to explore the optimal strategy for treating of HS-induced liver injury by intervening in bile acid metabolism.

In conclusion, our study indicates that supplementation of TUDCA with appropriate concentration exhibited protective effects on HS-induced liver injury. TUDCA could enhance the expression of SIRT1–FXR, which restored hepatocyte proliferation and inhibited hepatocyte apoptosis and inflammatory responses by downregulating the expression and acetylation of NF-κB and p53, as well as upregulating the expression of FoxM1. These results demonstrate that TUDCA might be a promising therapeutic for HS-induced liver injury.

Acknowledgments

The authors thank the staff of Shanghai Institute of Traumatology and Orthopedics for their technical support, and also thank LetPub (www.letpub.com) for providing linguistic assistance during the preparation of this manuscript.

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Keywords:

FXR; hemorrhagic shock; liver injury; SIRT1; TUDCA

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