Molecular Hydrogen Protects Against Ischemia-reperfusion Injury in a Mouse Fatty Liver Model Via Regulating HO-1 and Sirt1 Expression

Overview

Journal Sci Rep

Specialty Science

Date 2018 Sep 21

PMID 30232347

Citations 22

Authors

Shaowei Li

Masayuki Fujino

Naotsugu Ichimaru

Ryosuke Kurokawa

Shinichi Hirano

Lisha Mou

Shiro Takahara

Terumi Takahara

Xiao-Kang Li

Affiliations

Soon will be listed here.

Abstract

Fatty liver has lower tolerance against ischemia-reperfusion (I/R) injury in liver operations, including liver transplantation. Seeking to ameliorate liver injury following I/R in fatty liver, we examined the protective effect of hydrogen (H) saline on I/R liver injury in a methionine and choline-deficient plus high fat (MCDHF) diet-induced fatty liver mouse model. Saline containing 7 ppm H was administrated during the process of I/R. Livers were obtained and analyzed. Primary hepatocytes and Kupffer cells (KCs) were obtained from fatty liver and subjected to hypoxia/reoxygenation. Apoptosis-related proteins and components of the signaling pathway were analyzed after treatment with hydrogen gas. The MCDHF I/R group showed higher levels of AST and ALT in serum, TUNEL-positive apoptotic cells, F4/80 immunopositive cells, mRNA levels of inflammatory cytokines, constituents of the signaling pathway, pro-apoptotic molecules in liver, and KCs and/or primary hepatocytes, compared to the control group. In contrast, H treatment significantly suppressed the signs of I/R injury in fatty liver. Moreover, the expression of Bcl-2, HO-1, and Sirt1 in liver, KCs, and hepatocytes by hydrogen gas were increased, whereas caspase activation, Bax, and acetylation of p53 were suppressed by hydrogen gas. These results demonstrated that H treatment ameliorated I/R liver injury in a fatty liver model by reducing hepatocyte apoptosis, inhibiting macrophage activation and inflammatory cytokines, and inducing HO-1 and Sirt1 expression. Taken togather, treatment with H saline may have a protective effect and safe therapeutic activity during I/R events, such as in liver transplantation with fatty liver.

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References

Jaeschke H, Lemasters J . Apoptosis versus oncotic necrosis in hepatic ischemia/reperfusion injury. Gastroenterology. 2003; 125(4):1246-57. DOI: 10.1016/s0016-5085(03)01209-5. View

Farghali H, Kutinova Canova N, Lekic N . Resveratrol and related compounds as antioxidants with an allosteric mechanism of action in epigenetic drug targets. Physiol Res. 2012; 62(1):1-13. DOI: 10.33549/physiolres.932434. View

Han S, Kim G, Lee S, Kwon C, Gwak M, Lee S . Comparison of the tolerance of hepatic ischemia/reperfusion injury in living donors: macrosteatosis versus microsteatosis. Liver Transpl. 2014; 20(7):775-83. DOI: 10.1002/lt.23878. View

Shuh M, Bohorquez H, Loss Jr G, Cohen A . Tumor Necrosis Factor-α: Life and Death of Hepatocytes During Liver Ischemia/Reperfusion Injury. Ochsner J. 2013; 13(1):119-30. PMC: 3603175. View

Li S, Takahara T, Fujino M, Fukuhara Y, Sugiyama T, Li X . Astaxanthin prevents ischemia-reperfusion injury of the steatotic liver in mice. PLoS One. 2017; 12(11):e0187810. PMC: 5679630. DOI: 10.1371/journal.pone.0187810. View

Mosher B, Dean R, Harkema J, Remick D, Palma J, Crockett E . Inhibition of Kupffer cells reduced CXC chemokine production and liver injury. J Surg Res. 2001; 99(2):201-10. DOI: 10.1006/jsre.2001.6217. View

Zheng X, Mao Y, Cai J, Li Y, Liu W, Sun P . Hydrogen-rich saline protects against intestinal ischemia/reperfusion injury in rats. Free Radic Res. 2009; 43(5):478-84. DOI: 10.1080/10715760902870603. View

Chen D, Steele A, Lindquist S, Guarente L . Increase in activity during calorie restriction requires Sirt1. Science. 2005; 310(5754):1641. DOI: 10.1126/science.1118357. View

Rickenbacher A, Jang J, Limani P, Ungethum U, Lehmann K, Oberkofler C . Fasting protects liver from ischemic injury through Sirt1-mediated downregulation of circulating HMGB1 in mice. J Hepatol. 2014; 61(2):301-8. DOI: 10.1016/j.jhep.2014.04.010. View

10.

Kulik U, Lehner F, Klempnauer J, Borlak J . Primary non-function is frequently associated with fatty liver allografts and high mortality after re-transplantation. Liver Int. 2017; 37(8):1219-1228. DOI: 10.1111/liv.13404. View

11.

Takahashi A, Masuda A, Sun M, Centonze V, Herman B . Oxidative stress-induced apoptosis is associated with alterations in mitochondrial caspase activity and Bcl-2-dependent alterations in mitochondrial pH (pHm). Brain Res Bull. 2004; 62(6):497-504. DOI: 10.1016/j.brainresbull.2003.07.009. View

12.

Luo J, Nikolaev A, Imai S, Chen D, Su F, SHILOH A . Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell. 2001; 107(2):137-48. DOI: 10.1016/s0092-8674(01)00524-4. View

13.

Li S, Takahara T, Li X, Fujino M, Sugiyama T, Tsukada K . 5-Aminolevulinic acid combined with ferrous iron ameliorate ischemia-reperfusion injury in the mouse fatty liver model. Biochem Biophys Res Commun. 2016; 470(4):900-6. DOI: 10.1016/j.bbrc.2016.01.136. View

14.

Ge L, Wei L, Du C, Song G, Xue Y, Shi H . Hydrogen-rich saline attenuates spinal cord hemisection-induced testicular injury in rats. Oncotarget. 2017; 8(26):42314-42331. PMC: 5522069. DOI: 10.18632/oncotarget.15876. View

15.

Hool L . Reactive oxygen species in cardiac signalling: from mitochondria to plasma membrane ion channels. Clin Exp Pharmacol Physiol. 2006; 33(1-2):146-51. DOI: 10.1111/j.1440-1681.2006.04341.x. View

16.

Lai Y, Chen W, Kuo T, Ho C, Kuo C, Tseng Y . Mass-Spectrometry-Based Serum Metabolomics of a C57BL/6J Mouse Model of High-Fat-Diet-Induced Non-alcoholic Fatty Liver Disease Development. J Agric Food Chem. 2015; 63(35):7873-84. DOI: 10.1021/acs.jafc.5b02830. View

17.

Choi Y, Kim J, Lee D, Lee K, Won M, Jeoung D . Carbon Monoxide Potentiation of L-Type Ca Channel Activity Increases HIF-1α-Independent VEGF Expression via an AMPKα/SIRT1-Mediated PGC-1α/ERRα Axis. Antioxid Redox Signal. 2016; 27(1):21-36. DOI: 10.1089/ars.2016.6684. View

18.

Xin H, Zhang B, Wu Z, Hang X, Xu W, Ni W . Consumption of hydrogen-rich water alleviates renal injury in spontaneous hypertensive rats. Mol Cell Biochem. 2014; 392(1-2):117-24. DOI: 10.1007/s11010-014-2024-4. View

19.

Cai J, Kang Z, Liu K, Liu W, Li R, Zhang J . Neuroprotective effects of hydrogen saline in neonatal hypoxia-ischemia rat model. Brain Res. 2008; 1256:129-37. DOI: 10.1016/j.brainres.2008.11.048. View

20.

Kawamura T, Wakabayashi N, Shigemura N, Huang C, Masutani K, Tanaka Y . Hydrogen gas reduces hyperoxic lung injury via the Nrf2 pathway in vivo. Am J Physiol Lung Cell Mol Physiol. 2013; 304(10):L646-56. PMC: 3652058. DOI: 10.1152/ajplung.00164.2012. View