Volume 24, Issue 5 pp. 645-654

Original Article

Free Access

CAAT/enhancer binding protein–homologous protein deficiency attenuates liver ischemia/reperfusion injury in mice

Seidai Wada,

Seidai Wada

Departments of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan

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Etsuro Hatano,

Corresponding Author

Etsuro Hatano

[email protected]

Departments of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan

Department of Surgery, Hyogo College of Medicine, Hyogo, Japan

Address reprint requests to Etsuro Hatano, M.D., Ph.D., Department of Surgery, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan. Telephone: +81-798-45-6582; FAX: +81-798-45-6581; E-mail: [email protected]Search for more papers by this author

Tomoaki Yoh,

Tomoaki Yoh

Departments of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan

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Naohiko Nakamura,

Naohiko Nakamura

Departments of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan

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Yukihiro Okuda,

Yukihiro Okuda

Departments of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan

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Masayuki Okuno,

Masayuki Okuno

Departments of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan

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Yosuke Kasai,

Yosuke Kasai

Departments of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan

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Keiko Iwaisako,

Keiko Iwaisako

Department of Target Therapy Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

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Satoru Seo,

Satoru Seo

Departments of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan

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Kojiro Taura,

Kojiro Taura

Departments of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan

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Shinji Uemoto,

Shinji Uemoto

Departments of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan

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Seidai Wada,

Seidai Wada

Departments of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan

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Etsuro Hatano,

Corresponding Author

Etsuro Hatano

[email protected]

Departments of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan

Department of Surgery, Hyogo College of Medicine, Hyogo, Japan

Tomoaki Yoh,

Tomoaki Yoh

Departments of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan

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Naohiko Nakamura,

Naohiko Nakamura

Departments of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan

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Yukihiro Okuda,

Yukihiro Okuda

Departments of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan

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Masayuki Okuno,

Masayuki Okuno

Departments of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan

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Yosuke Kasai,

Yosuke Kasai

Departments of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan

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Keiko Iwaisako,

Keiko Iwaisako

Department of Target Therapy Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

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Satoru Seo,

Satoru Seo

Departments of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan

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Kojiro Taura,

Kojiro Taura

Departments of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan

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Shinji Uemoto,

Shinji Uemoto

Departments of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan

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First published: 10 March 2018

https://doi.org/10.1002/lt.25053

Citations: 7

Potential conflict of interest: Nothing to report.

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Abstract

Ischemia/reperfusion injury (IRI) is one of the main causes of liver dysfunction after liver surgery. Involvement of endoplasmic reticulum (ER) stress in various diseases has been demonstrated, and CAAT/enhancer binding protein–homologous protein (CHOP) is a transcriptional regulator that is induced by ER stress. It is also a key regulator of ER stress-mediated apoptosis. The aim of this study was to investigate the role of CHOP in liver IRI. Wild type (WT) and CAAT/enhancer binding protein–homologous protein knockout (CHOP–/–) mice were subjected to 70% liver warm ischemia/reperfusion for 60 minutes. At different times after reperfusion, liver tissues and blood samples were collected for evaluation. Induction of ER stress including CHOP expression was ascertained. Liver damage was evaluated based on serum liver enzymes, liver histology, and neutrophil infiltration. Hepatocyte death including apoptosis was assessed. Liver warm IRI induced ER stress in both WT and CHOP–/– mice. In addition, CHOP expression was up-regulated in WT mice. At 6 hours after reperfusion, liver damage was attenuated in CHOP–/– mice. On the basis of terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling staining, apoptotic and necrotic cells were significantly reduced in CHOP–/– mice. CHOP deficiency also reduced the cleavage of caspase 3 and expression of the proapoptotic protein B cell lymphoma 2–associated X protein. Liver IRI induces CHOP expression, and CHOP deficiency attenuates liver IRI by inhibiting apoptosis. Elucidation of the function of CHOP in liver IRI may contribute to further investigation for a therapy against liver IRI associated with the ER stress pathway. Liver Transplantation 24 645–654 2018 AASLD.

Abbreviations

ATF4: activating transcription factor 4
ALT: alanine aminotransferase
AST: aspartate aminotransferase
BAX: B cell lymphoma 2–associated X protein
BCL2: B cell lymphoma 2
BCL-x_L: B cell lymphoma extra large
CHOP: CAAT/enhancer binding protein–homologous protein
CHOP–/–: CAAT/enhancer binding protein–homologous protein knockout
ER: endoplasmic reticulum
GRP78: glucose-regulated protein 78
H & E: hematoxylin-eosin
HPF: high-power field
HPRT: hypoxanthine phosphoribosyltransferase
IL: interleukin
I/R: ischemia/reperfusion
IRI: ischemia/reperfusion injury
MPO: myeloperoxidase
mRNA: messenger RNA
N.S.: not significant
RT-PCR: real-time polymerase chain reaction
SE: standard error
TUNEL: terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling
UPR: unfolded protein response
WT: wild type

Liver ischemia/reperfusion injury (IRI) occurs in liver transplantation, liver resection (the Pringle maneuver or massive bleeding), and hemorrhagic and cardiogenic shock.1, 2 This results in liver dysfunction and failure, which can even lead to death via multiorgan system failure. Furthermore, tissue damage of the liver parenchyma induced by ischemia/reperfusion (I/R) can potentially lead to postoperative cancer recurrence.3-7

The forms of cell death that occur during liver I/R have been debated. On the basis of morphological assessment by hematoxylin-eosin (H & E) and terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining, most hepatocyte death occurs via necrosis.8, 9 However, necrosis and apoptosis have common features and mechanisms. In addition, the initiation of the apoptotic process can be converted to necrosis upon adenosine triphosphate depletion at several stages of cell death. Moreover, it is sometimes difficult to distinguish between these 2 forms.10 On the other hand, Rüdiger et al. reported that apoptosis is the central mechanism of liver IRI.11 Additionally, many antiapoptotic strategies against liver IRI have been reported.12 Therefore, it is reasonable to approach liver IRI from the viewpoint of apoptosis.

Under various abnormal conditions, endoplasmic reticulum (ER) function, which folds newly synthesized proteins, is depressed and unfolded, or misfolded proteins accumulate in the lumen of ER. This situation is referred to as ER stress. The involvement of ER stress in various diseases has been reported, including neurodegenerative disease, diabetes mellitus,13 cardiovascular disease,14 and chronic kidney disease.15 The unfolded protein response (UPR) is a protective mechanism that mitigates ER stress.16 Accumulated unfolded proteins are eliminated by the UPR in 3 ways:

Up-regulation of ER chaperones to assist protein folding.
Transcriptional attenuation.
Degradation of unfolded proteins.

However, when ER stress surpasses this protective mechanism, apoptosis is induced. During ER stress-mediated apoptosis, transcriptional factor CAAT/enhancer binding protein–homologous protein (CHOP) plays an important role.17

In CAAT/enhancer binding protein–homologous protein knockout (CHOP–/–) mice, the improvement of various pathological conditions has been reported. Decreased liver damage in CHOP–/– mice has been shown in an intragastric ethanol feeding model,18 cholestasis-induced liver fibrosis model,19 and LPS-induced acute liver failure model.20 IRI in the myocardium,21 kidney,22-25 and neuronal cells26 was also shown to be attenuated in CHOP–/– mice. However, the relationship between CHOP and liver IRI has not been shown. Thus, the aim of this study was to clarify whether CHOP deficiency can attenuate liver IRI.

Materials and Methods

ANIMALS

Male C57BL/6 (age, 7-11 weeks; Japan SLC, Tokyo, Japan) and CHOP–/– mice (age, 7-11 weeks; C57BL/6 background) were used. CHOP–/– mice were provided by Professor Tomomi Goto (Kumamoto University, Kumamoto, Japan). Food and water were administered ad libitum, and mice were maintained under constant environmental conditions with a 12 hours/12 hours light-dark cycle. Protocols for all experiments were approved by the animal research committee of Kyoto University. Animals were cared for in accordance with the National Institutes of Health's Guide for the Care and Use of Laboratory Animals.

LIVER WARM IRI MODEL

Mice were anesthetized by isoflurane inhalation and placed on a heating plate to maintain their body temperature during operation. After laparotomy, the vessels supplying 70% of the left side of the liver were disrupted using a micro atraumatic vascular clamp, and subsequently, the abdomen was closed. Before closure, sodium pentobarbital (60 mg/kg) was administered intraperitoneally for sedation during the period of ischemia. After 60 minutes, the clamp was removed, and reperfusion was initiated. Sham control mice underwent the same procedure without vascular occlusion. Mice were sacrificed at different time points after reperfusion, and liver tissue and blood were collected.

ASSESSMENT OF HEPATOCELLULAR DAMAGE

Serum aspartate aminotransferase (AST) and serum alanine aminotransferase (ALT) levels were measured to assess hepatocellular damage.

LIVER HISTOLOGY

Formalin-fixed, paraffin-embedded sections were cut at a thickness of 4 μm, and the slides were stained with H & E. Histological damage by liver I/R was blindly scored with Suzuki's criteria on a scale from 0 to 4.27

TUNEL ASSAY

TUNEL assays were performed on 4-μm sections using an Apoptosis in situ Detection Kit (Wako, Osaka, Japan) to detect apoptotic and necrotic cells in liver tissues 6 hours after reperfusion. The number of TUNEL-positive cells was counted in 10 randomly selected high-power fields (HPFs; magnification, ×400) per slide (n = 5 per group).

QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION

Total RNA was extracted from liver tissue using TRIzol (Invitrogen Japan, Tokyo, Japan) and the RNeasy Mini Kit with on-column DNA digestion (Qiagen, Valencia, CA). In accordance with the manufacturers' protocol, total RNA was reverse transcribed to complementary DNA using an Omniscript RT Kit (Qiagen, Valencia, CA) with oligo (dT)_8-12 primers (Invitrogen Japan). Quantitative real-time polymerase chain reaction (RT-PCR) was performed with a KAPA SYBR FAST qPCR Kit (Nippon Genetics, Tokyo, Japan) and StepOnePlus system (Applied Biosystems, Foster City, CA). The primers used in this study are shown in Table 1. Expression levels are provided as relative ratios to the expression level of hypoxanthine phosphoribosyltransferase (HPRT).

Table 1. Sequences of Primers Used for RT-PCR

Target	Forward	Reverse
CHOP	5′-TATCTCATCCCCAGGAAACG	5′-GGGCACTGACCACTCTGTTT
GRP78	5′-GAAAGGATGGTTAATGATGCTGAG	5′-GTCTTCAATGTCCGCATCCTG
ATF4	5′-ATGGCCGGCTATGGATGAT	5′-CGAAGTCAAACTCTTTCAGATCCATT
HPRT	5′-TCAACGGGGGACATAAAAGT	5′-TGCATTGTTTTACCAGTGTCAA

WESTERN BLOT ANALYSIS

Western blot analysis was conducted as previously described,28 using the following primary antibodies and dilutions: anti-GADD153 (CHOP; number sc-7351; Santa Cruz Biotechnology, Santa Cruz, CA) at 1:200; anti-cleaved caspase 3 (number 9664; Cell Signaling Technology, Danvers, MA) at 1:1000; anti–B cell lymphoma 2–associated X protein (BAX; number 2772; Cell Signaling Technology) at 1:1000; anti–B cell lymphoma extra large (BCL-x_L; number 2762; Cell Signaling Technology) at 1:1000; anti–B cell lymphoma 2 (BCL2; number sc-7382; Santa Cruz Biotechnology) at 1:500; and anti-β-actin antibody (number sc-47778, Santa Cruz Biotechnology) at 1:1000. The intensity of the bands was quantified with ImageJ.

IMMUNOHISTOCHEMISTRY

The specimens were fixed in 10% formalin and embedded in paraffin. Subsequently, they were deparaffinized, and endogenous peroxidase was quenched with 3% hydrogen peroxide in phosphate-buffered saline at room temperature for 10 minutes. The antigen was retrieved by incubation in a citric acid buffer at 120°C for 10 minutes. After being blocked, the sections were incubated with the primary antibody recognizing anti-CHOP (ab11419; Abcam) diluted at 1:100 at room temperature for 2 hours and anti-myeloperoxidase (MPO; ab9535; Abcam) diluted at 1:50 at 4°C overnight and then with labeled polymer in an envision + system horseradish peroxidase (Dako Japan, Tokyo, Japan) at room temperature for 1 hour. The sections were examined after incubation with a liquid 3,3′-diaminobenzidine substrate chromogen system (Dako Japan) for 5 minutes.

STATISTICAL ANALYSIS

All data are expressed as mean ± SE. Statistical analysis was performed using Student t test to compare mean values between groups. A P value < 0.05 was considered statistically significant. Analyses were performed by JMP pro 11 (SAS Institute, Cary, NC).

Results

CHOP EXPRESSION INCREASES IN WILD TYPE MICE FOLLOWING LIVER IRI

Wild type (WT) mice subjected to liver IRI were sacrificed 3 and 6 hours after reperfusion to ascertain whether this condition up-regulates CHOP expression in the mouse liver. RT-PCR demonstrated that CHOP messenger RNA (mRNA) expression increased by 16-fold at 3 hours after reperfusion compared with that in sham-operated mice (Fig. 1A). Consistent with mRNA levels, CHOP protein expression was elevated at 3 and 6 hours after reperfusion by Western blotting, whereas the CHOP protein was only minimally expressed in sham-operated mice (Fig. 1B). Then, to clarify which cell type within the liver up-regulates CHOP after I/R, we performed immunohistochemical staining for CHOP. In sham-operated livers, CHOP protein was faintly expressed in the cytosol of hepatocytes. Three hours after reperfusion, CHOP was strongly expressed in the cytosol and nucleus of hepatocytes, whereas nonparenchymal cells were not stained. At 6 hours after reperfusion, CHOP expression of hepatocytes decreased compared with that at 3 hours after reperfusion. CHOP expression of the cytoplasm diminished, whereas the nucleus stained strongly, and nonparenchymal cells also expressed CHOP (Fig. 1C).

Details are in the caption following the image — **Figure 1**
Open in figure viewer PowerPoint

Liver warm IRI induces CHOP expression in WT mice. WT mice were subjected to 70% liver I/R for 60 minutes and were sacrificed at 3 and 6 hours after reperfusion. (A) Quantitative RT-PCR and (B) Western bolt analysis of CHOP expression. (C) Immunohistochemistry of CHOP expression. Data are shown as the mean ± SE (n = 3). *P < 0.05. Sham: sham-operated mice.

IRI INDUCES ER STRESS IN BOTH WT AND CHOP–/– MICE

To confirm whether ER stress is induced by liver IRI in both WT and CHOP–/– mice, animals were sacrificed 3 and 6 hours after reperfusion. The ER stress marker glucose-regulated protein 78 (GRP78) was assessed by RT-PCR. GRP78 expression was significantly increased 3 hours after reperfusion in both WT and CHOP–/– mice. Three hours after reperfusion, GRP78 expression slightly increased in CHOP–/– mice, compared with that in WT mice (Fig. 2A). The activating transcription factor 4 (ATF4)-CHOP pathway, which is known to be the main pathway for CHOP induction, was also activated. The mRNA level of ATF4, which is upstream of CHOP, also increased 3 hours after reperfusion in both WT and CHOP–/– mice (Fig. 2B). Similar to CHOP expression, GRP78 and ATF4 mRNA expression peaked at 3 hours after reperfusion. These results indicated that liver IRI induces ER stress in both WT and CHOP–/– mice.

CHOP DEFICIENCY ATTENUATES LIVER IRI

To test whether CHOP deficiency attenuates liver damage induced by I/R, liver sections and blood samples from animals 6 hours after I/R were evaluated. Serum AST and ALT levels were significantly increased in WT mice (ALT, 8438 ± 699 IU/L; AST, 3788 ± 313 IU/L) compared with that in CHOP–/– mice (ALT, 5084 ± 830 IU/L; AST, 2543 ± 260 IU/L) at 6 hours after reperfusion (P < 0.05; Fig. 3A). On the basis of H & E staining of livers 6 hours after reperfusion, extended necrotic areas and vacuolization were attenuated in CHOP-deficient mice compared with WT mice. The Suzuki score significantly decreased in CHOP–/– mice (Fig. 3B). Then, we assessed neutrophil infiltration induced by liver IRI by immunohistochemical staining for MPO. Numbers of MPO-positive cells were significantly decreased in the livers of CHOP–/– mice at 6 hours after reperfusion as compared with WT mice (Fig. 3C).

LIVER IRI–INDUCED APOPTOSIS AND NECROSIS ARE DECREASED IN CHOP–/– MICE

We next evaluated hepatocyte death induced by IRI at 6 hours after reperfusion in both WT and CHOP–/– mice. The number of TUNEL-positive cells was significantly decreased in CHOP–/– mice (47 ± 6 [WT] versus 24 ± 2 [CHOP–/–] per HPF; P < 0.05). Most of the TUNEL-positive cells were hepatocytes, and both the nucleus and cytoplasm were stained, demonstrating a staining pattern indicative of necrotic cells (Fig. 4A). To ascertain whether apoptosis was involved in this process, cleaved caspase 3 was analyzed by Western blotting. Cleaved caspase 3 was expressed at a low level in sham-operated mice. Cleaved caspase 3 expression increased after I/R in both groups of animals. However, the expression of this marker was significantly higher in WT mice than in CHOP–/– mice (Fig. 4B).

CHOP DEFICIENCY ATTENUATES HEPATOCYTE APOPTOSIS INDUCED BY IRI THROUGH THE INTRINSIC APOPTOSIS PATHWAY

The expression levels of BCL2 family proteins—BCL2, BCL-x_L, and BAX—were determined by Western blotting. Compared with that in sham-operated mice, the expression of the antiapoptotic proteins BCL2 and BCL-x_L decreased, and the expression of the proapoptotic protein BAX was increased at 6 hours after reperfusion. After IRI, BAX expression was significantly suppressed in CHOP–/– mice compared with that in WT mice (Fig. 5A). Meanwhile, BCL2 was expressed at a slightly higher level in CHOP–/– mice than in WT mice, and the expression of BCL-x_L was virtually identical in both groups (Fig. 5B,C).

Discussion

Several relationships between ER stress and liver IRI have been reported. The small molecule chaperone 4-phenyl butyric acid, which ameliorates ER stress, improves liver IRI.29, 30 In addition, some drugs attenuate liver IRI via the ER stress pathway.31 Improvement of liver IRI by inhibiting the ER stress pathway, involving CHOP, has also been reported.32 Furthermore, in an animal model of traumatic hemorrhagic shock, which can be regarded as a mild liver I/R model, ER stress was induced to a greater extent than oxidative stress. This suggests a deep involvement of ER stress and liver IRI.33

The relationship between CHOP and IRI of other organs has also been reported. In the kidney and cerebellum, elevation of CHOP expression induced by IRI continues until after 24 hours,22, 34 whereas CHOP expression peaks at 0.5 hours after reperfusion in myocardial reperfusion injury.21 In our liver IRI model, CHOP expression peaked at 3 hours after reperfusion at mRNA and protein levels. However, immunohistochemistry revealed that liver nonparenchymal cells expressed CHOP later than hepatocytes, in which CHOP expression peaked at 3 hours after reperfusion. Although improvement of liver injury was mild, we confirm that CHOP deficiency attenuates IRI of the liver as shown in other organs.

CHOP regulates the intrinsic apoptosis pathway via BCL2 family proteins, and these proteins, including BCL2, BCL-x_L, and BAX, are involved in liver IRI.35-37 Our results show that liver IRI was attenuated in CHOP-deficient mice through the inhibition of BAX expression and the attenuation of apoptosis. The proapoptotic molecule BAX, which stimulates cytochrome c release from mitochondria and increases caspase 3 activity, occurs downstream of CHOP and plays an important role in CHOP-mediated apoptosis. In addition, BAX can induce apoptosis independent of other antiapoptotic molecules.35 Ben-Ari et al. showed that liver IRI was attenuated in BAX–/– mice.35 Recently, the relationship between CHOP and inflammation has been reported. In IRI, inflammatory cytokines such as tumor necrosis factor α, interleukin (IL) 6, and IL1β were suppressed in myocardia of CHOP–/– mice,21 and IL1β was also suppressed in kidney tissue of CHOP–/– mice.22 In a study of steatohepatitis, the relationship between CHOP and the nuclear factor kappa B pathway was shown in human primary hepatocyte.38 We assessed the inflammatory response including these cytokines and pathways, but we could not find a significant difference between the groups. However, the significant difference in neutrophil infiltration in both groups suggested the involvement of CHOP in some inflammatory response. One of the reasons for this result is probably the mildness of improvement of liver damage in this study.

However, it should be carefully considered whether inhibiting the UPR itself leads to alleviation of liver IRI in clinical practice. Zhou et al. showed that the role of the UPR in the mouse liver I/R model differs between a 30-minute ischemia group and a 90-minute ischemia group. Specifically, this response was pathogenic in the 90-minute ischemia model but was protective in the 30-minute group.39 This report reminds us that the UPR is originally a protective mechanism. In the clinical setting, severe liver damage, as induced in the animal model of warm IRI, is rare because liver resection is carefully performed to mitigate postoperative liver failure, and hemorrhagic and cardiogenic shock are not a complete interruption of the blood flow. During liver resection, moderate IRI in small remnants of the liver causes liver failure, not severe IRI itself. Portal clamping6 or intraoperative blood loss40, 41 might affect tumor recurrence even if they are not fatal during the acute phase. For these reasons, liver warm IRI needs to be improved, even if it does not readily occur with severity. Meanwhile, because the degree of liver damage is different from that of the animal model, we must carefully address the relationship between the UPR and liver IRI in clinical situations. Elucidation of the function of CHOP in liver IRI should facilitate the investigation of this relationship.

After renal IRI in CHOP–/– mice, several mechanisms for ameliorating injury have been reported.22-25 Noh et al. showed that the BAX/BCL2 ratio is significantly decreased in the I/R kidney in CHOP–/– mice.22 In contrast, Chen et al. did not find any significant difference in the expression of BAX and BCL2 between CHOP–/– and WT mice.25 Noh et al. suggested that this difference was due to the degree of kidney injury. In the future, further elucidation is also expected regarding the mechanism through which liver IRI is alleviated in CHOP–/– mice.22

In conclusion, we have for the first time shown that CHOP deficiency attenuates liver IRI. These results may contribute to further investigation of a therapy against liver IRI associated with the ER stress pathway.

REFERENCES

1 Lentsch AB, Kato A, Yoshidome H, McMasters KM, Edwards MJ. Inflammatory mechanisms and therapeutic strategies for warm hepatic ischemia/reperfusion injury. Hepatology 2000; 32: 169-173.
10.1053/jhep.2000.9323
CAS PubMed Web of Science® Google Scholar
2 Abu-Amara M, Yang SY, Tapuria N, Fuller B, Davidson B, Seifalian A. Liver ischemia/reperfusion injury: processes in inflammatory networks--a review. Liver Transpl 2010; 16: 1016-1032.
10.1002/lt.22117
CAS PubMed Web of Science® Google Scholar
3 Doi K, Horiuchi T, Uchinami M, Tabo T, Kimura N, Yokomachi J, et al. Hepatic ischemia-reperfusion promotes liver metastasis of colon cancer. J Surg Res 2002; 105: 243-247.
10.1006/jsre.2002.6356
CAS PubMed Web of Science® Google Scholar
4 Man K, Ng KT, Lo CM, Ho JW, Sun BS, Sun CK, et al. Ischemia-reperfusion of small liver remnant promotes liver tumor growth and metastases--activation of cell invasion and migration pathways. Liver Transpl 2007; 13: 1669-1677.
10.1002/lt.21193
CAS PubMed Web of Science® Google Scholar
5 Orci LA, Lacotte S, Oldani G, Morel P, Mentha G, Toso C. The role of hepatic ischemia-reperfusion injury and liver parenchymal quality on cancer recurrence. Dig Dis Sci 2014; 59: 2058-2068.
10.1007/s10620-014-3182-7
PubMed Web of Science® Google Scholar
6 Nijkamp MW, van der Bilt JD, Snoeren N, Hoogwater FJ, van Houdt WJ, Molenaar IQ, et al. Prolonged portal triad clamping during liver surgery for colorectal liver metastases is associated with decreased time to hepatic tumour recurrence. Eur J Surg Oncol 2010; 36: 182-188.
10.1016/j.ejso.2009.10.016
CAS PubMed Web of Science® Google Scholar
7 Iguchi K, Hatano E, Yamanaka K, Tanaka S, Taura K, Uemoto S. The impact of posthepatectomy liver failure on the recurrence of hepatocellular carcinoma. World J Surg 2014; 38: 150-158.
10.1007/s00268-013-2247-7
PubMed Web of Science® Google Scholar
8 Gujral JS, Bucci TJ, Farhood A, Jaeschke H. Mechanism of cell death during warm hepatic ischemia-reperfusion in rats: apoptosis or necrosis? Hepatology 2001; 33: 397-405.
10.1053/jhep.2001.22002
CAS PubMed Web of Science® Google Scholar
9 Eum HA, Cha YN, Lee SM. Necrosis and apoptosis: sequence of liver damage following reperfusion after 60 min ischemia in rats. Biochem Biophys Res Commun 2007; 358: 500-505.
10.1016/j.bbrc.2007.04.153
CAS PubMed Web of Science® Google Scholar
10 Jaeschke H, Lemasters JJ. Apoptosis versus oncotic necrosis in hepatic ischemia/reperfusion injury. Gastroenterology 2003; 125: 1246-1257.
10.1016/S0016-5085(03)01209-5
CAS PubMed Web of Science® Google Scholar
11 Rüdiger HA, Graf R, Clavien PA. Liver ischemia: apoptosis as a central mechanism of injury. J Invest Surg 2003; 16: 149-159.
PubMed Web of Science® Google Scholar
12 Georgiev P, Dahm F, Graf R, Clavien PA. Blocking the path to death: anti-apoptotic molecules in ischemia/reperfusion injury of the liver. Curr Pharm Des 2006; 12: 2911-2921.
10.2174/138161206777947588
CAS PubMed Web of Science® Google Scholar
13 Oyadomari S, Takeda K, Takiguchi M, Gotoh T, Matsumoto M, Wada I, et al. Nitric oxide-induced apoptosis in pancreatic beta cells is mediated by the endoplasmic reticulum stress pathway. Proc Natl Acad Sci U S A 2001; 98: 10845-10850.
10.1073/pnas.191207498
CAS PubMed Web of Science® Google Scholar
14 Minamino T, Kitakaze M. ER stress in cardiovascular disease. J Mol Cell Cardiol 2010; 48: 1105-1110.
10.1016/j.yjmcc.2009.10.026
CAS PubMed Web of Science® Google Scholar
15 Maekawa H, Inagi R. Stress signal network between hypoxia and ER stress in chronic kidney disease. Front Physiol 2017; 8: 74.
10.3389/fphys.2017.00074
PubMed Web of Science® Google Scholar
16 Mori K. Tripartite management of unfolded proteins in the endoplasmic reticulum. Cell 2000; 101: 451-454.
10.1016/S0092-8674(00)80855-7
CAS PubMed Web of Science® Google Scholar
17 Oyadomari S, Mori M. Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ 2004; 11: 381-389.
10.1038/sj.cdd.4401373
CAS PubMed Web of Science® Google Scholar
18 Ji C, Mehrian-Shai R, Chan C, Hsu YH, Kaplowitz N. Role of CHOP in hepatic apoptosis in the murine model of intragastric ethanol feeding. Alcohol Clin Exp Res 2005; 29: 1496-1503.
10.1097/01.alc.0000174691.03751.11
CAS PubMed Web of Science® Google Scholar
19 Tamaki N, Hatano E, Taura K, Tada M, Kodama Y, Nitta T, et al. CHOP deficiency attenuates cholestasis-induced liver fibrosis by reduction of hepatocyte injury. Am J Physiol Gastrointest Liver Physiol 2008; 294: G498-G505.
10.1152/ajpgi.00482.2007
CAS PubMed Web of Science® Google Scholar
20 Rao J, Zhang C, Wang P, Lu L, Qian X, Qin J, et al. C/EBP homologous protein (CHOP) contributes to hepatocyte death via the promotion of ERO1α signalling in acute liver failure. Biochem J 2015; 466: 369-378.
10.1042/BJ20140412
CAS PubMed Web of Science® Google Scholar
21 Miyazaki Y, Kaikita K, Endo M, Horio E, Miura M, Tsujita K, et al. C/EBP homologous protein deficiency attenuates myocardial reperfusion injury by inhibiting myocardial apoptosis and inflammation. Arterioscler Thromb Vasc Biol 2011; 31: 1124-1132.
10.1161/ATVBAHA.111.224519
CAS PubMed Web of Science® Google Scholar
22 Noh MR, Kim JI, Han SJ, Lee TJ, Park KM. C/EBP homologous protein (CHOP) gene deficiency attenuates renal ischemia/reperfusion injury in mice. Biochim Biophys Acta 2015; 1852: 1895-1901.
10.1016/j.bbadis.2015.06.004
CAS PubMed Web of Science® Google Scholar
23 Dong B, Zhou H, Han C, Yao J, Xu L, Zhang M, et al. Ischemia/reperfusion-induced CHOP expression promotes apoptosis and impairs renal function recovery: the role of acidosis and GPR4. PloS One 2014; 9: e110944.
10.1371/journal.pone.0110944
PubMed Web of Science® Google Scholar
24 Yang JR, Yao FH, Zhang JG, Ji ZY, Li KL, Zhan J, et al. Ischemia-reperfusion induces renal tubule pyroptosis via the CHOP-caspase-11 pathway. Am J Physiol Renal Physiol 2014; 306: F75-F84.
10.1152/ajprenal.00117.2013
CAS PubMed Web of Science® Google Scholar
25 Chen BL, Sheu ML, Tsai KS, Lan KC, Guan SS, Wu CT, et al. CCAAT-enhancer-binding protein homologous protein deficiency attenuates oxidative stress and renal ischemia-reperfusion injury. Antioxid Redox Signal 2015; 23: 1233-1245.
10.1089/ars.2013.5768
CAS PubMed Web of Science® Google Scholar
26 Tajiri S, Oyadomari S, Yano S, Morioka M, Gotoh T, Hamada JI, et al. Ischemia-induced neuronal cell death is mediated by the endoplasmic reticulum stress pathway involving CHOP. Cell Death Differ 2004; 11: 403-415.
10.1038/sj.cdd.4401365
CAS PubMed Web of Science® Google Scholar
27 Suzuki S, Toledo-Pereyra LH, Rodriguez FJ, Cejalvo D. Neutrophil infiltration as an important factor in liver ischemia and reperfusion injury. Modulating effects of FK506 and cyclosporine. Transplantation 1993; 55: 1265-1272.
10.1097/00007890-199306000-00011
CAS PubMed Web of Science® Google Scholar
28 Okuno M, Hatano E, Nakamura K, Miyagawa-Hayashino A, Kasai Y, Nishio T, et al. Regorafenib suppresses sinusoidal obstruction syndrome in rats. J Surg Res 2015; 193: 693-703.
10.1016/j.jss.2014.08.052
CAS PubMed Web of Science® Google Scholar
29 Liu J, Ren F, Cheng Q, Bai L, Shen X, Gao F, et al. Endoplasmic reticulum stress modulates liver inflammatory immune response in the pathogenesis of liver ischemia and reperfusion injury. Transplantation 2012; 94: 211-217.
10.1097/TP.0b013e318259d38e
CAS PubMed Web of Science® Google Scholar
30 Vilatoba M, Eckstein C, Bilbao G, Smyth CA, Jenkins S, Thompson JA, et al. Sodium 4-phenylbutyrate protects against liver ischemia reperfusion injury by inhibition of endoplasmic reticulum-stress mediated apoptosis. Surgery 2005; 138: 342-351.
10.1016/j.surg.2005.04.019
PubMed Web of Science® Google Scholar
31 Zhu J, Hua X, Li D, Zhang J, Xia Q. Rapamycin attenuates mouse liver ischemia and reperfusion injury by inhibiting endoplasmic reticulum stress. Transplant Proc 2015; 47: 1646-1652.
10.1016/j.transproceed.2015.05.013
CAS PubMed Web of Science® Google Scholar
32 Rao J, Qin J, Qian X, Lu L, Wang P, Wu Z, et al. Lipopolysaccharide preconditioning protects hepatocytes from ischemia/reperfusion injury (IRI) through inhibiting ATF4-CHOP pathway in mice. PloS One 2013; 8: e65568.
10.1371/journal.pone.0065568
CAS PubMed Web of Science® Google Scholar
33 Duvigneau JC, Kozlov AV, Zifko C, Postl A, Hartl RT, Miller I, et al. Reperfusion does not induce oxidative stress but sustained endoplasmic reticulum stress in livers of rats subjected to traumatic-hemorrhagic shock. Shock 2010; 33: 289-298.
10.1097/SHK.0b013e3181aef322
PubMed Web of Science® Google Scholar
34 Poone GK, Hasseldam H, Munkholm N, Rasmussen RS, Grønberg NV, Johansen FF. The hypothermic influence on CHOP and Ero1-alpha in an endoplasmic reticulum stress model of cerebral ischemia. Brain Sci 2015; 5: 178-187.
10.3390/brainsci5020178
CAS PubMed Web of Science® Google Scholar
35 Ben-Ari Z, Pappo O, Cheporko Y, Yasovich N, Offen D, Shainberg A, et al. Bax ablation protects against hepatic ischemia/reperfusion injury in transgenic mice. Liver Transpl 2007; 13: 1181-1188.
10.1002/lt.21221
CAS PubMed Web of Science® Google Scholar
36 Honda K, Tohyama T, Kotegawa H, Kojima Y, Kushihata F, Watanabe J, Kobayashi N. Protective effect of adeno-mediated human Bcl-xL gene transfer to the mouse liver in a partial ischemia/reperfusion model. J Surg Res 2009; 157: e107-e116.
10.1016/j.jss.2008.10.019
CAS PubMed Web of Science® Google Scholar
37 Selzner M, Rüdiger HA, Selzner N, Thomas DW, Sindram D, Clavien PA. Transgenic mice overexpressing human Bcl-2 are resistant to hepatic ischemia and reperfusion. J Hepatol 2002; 36: 218-225.
10.1016/S0168-8278(01)00259-8
CAS PubMed Web of Science® Google Scholar
38 Willy JA, Young SK, Stevens JL, Masuoka HC, Wek RC. CHOP links endoplasmic reticulum stress to NF-κB activation in the pathogenesis of nonalcoholic steatohepatitis. Mol Biol Cell 2015; 26: 2190-2204.
10.1091/mbc.E15-01-0036
CAS PubMed Web of Science® Google Scholar
39 Zhou H, Zhu J, Yue S, Lu L, Busuttil RW, Kupiec-Weglinski JW, et al. The dichotomy of endoplasmic reticulum stress response in liver ischemia-reperfusion injury. Transplantation 2016; 100: 365-372.
10.1097/TP.0000000000001032
CAS PubMed Web of Science® Google Scholar
40 Jiang W, Fang YJ, Wu XJ, Wang FL, Lu ZH, Zhang RX, et al. Intraoperative blood loss independently predicts survival and recurrence after resection of colorectal cancer liver metastasis. PloS One 2013; 8: e76125.
10.1371/journal.pone.0076125
CAS PubMed Web of Science® Google Scholar
41 Katz SC, Shia J, Liau KH, Gonen M, Ruo L, Jarnagin WR, et al. Operative blood loss independently predicts recurrence and survival after resection of hepatocellular carcinoma. Ann Surg 2009; 249: 617-623.
10.1097/SLA.0b013e31819ed22f
PubMed Web of Science® Google Scholar

Citing Literature

Volume24, Issue5

May 2018

Pages 645-654

CAAT/enhancer binding protein–homologous protein deficiency attenuates liver ischemia/reperfusion injury in mice