Besides cardioprotective effects, the AT1R (angiotensin-II type 1 receptor) antagonist losartan protects the liver from IRI [IR (ischaemia/reperfusion) injury], but the mechanism has not been fully determined. The HIF (hypoxia inducible factor)-1α and Wnt/β-catenin signalling pathways have been reported to be involved in the mechanism of liver IRI. Therefore the aim of the present study was to determine whether the Wnt/HIF axis is part of the mechanism of the positive effect of AngII inhibition by losartan in liver IRI in rats. Various measurements were made in MCD/HF-NASH (methionine- and choline-deficient-diet/high-fat-diet-induced non-alcoholic steatohepatitis) rats with liver IRI. Acute losartan pre-administration markedly reversed the IR-suppressed levels of the hepatic-protective factors IL (interleukin)-6, IFN (interferon)-γ, Wnt3a, β-catenin and HIF-1α, and decreased hepatic blood flow and IR-elevated serum ALT (alanine aminotransferase), hepatic TNF (tumour necrosis factor)-α, IL-1α, hepatic congestion, vacuolization and necrosis, hepatic Suzuki IRI scores, necrotic index and levels of TBARS (thiobarbituric acid-reacting substances) in MCD/HF-NASH rats. Furthermore, acute Wnt3a pre-treatment significantly inhibited IR-elevated serum ALT, hepatic Suzuki IRI scores and TBARS, and restored the IR-depleted β-catenin/HIF-1α activity in MCD/HF-NASH rats. Simultaneous acute sFRP2 (secreted frizzled-related protein 2; a Wnt3a inhibitor) pre-treatment eliminated the losartan-related beneficial effects in MCD/HF-NASH rats with liver IRI, which was accompanied by a decrease in hepatic HIF-1α/β-catenin activity. Losartan-induced up-regulation of HIF-1α and Wnt/β-catenin signalling was associated with the recovery of IR-inhibited hepatic Bcl-2, Mn-SOD (manganese superoxide), Cu/Zn-SOD (copper/zinc superoxide) and GSH levels, and the suppression of IR-increased hepatic catalase and caspase 3/caspase 8 levels in MCD/HF-NASH rats. In conclusion, up-regulation of the HIF-1α and Wnt/β-catenin signalling pathways are part of the mechanism of the positive effects of losartan-related AngII inhibition in MCD/HF-NASH rats with liver IRI. Our study highlights the potential of the dual-organ protective agent losartan in NASH patients with steatotic livers and cardiovascular risk.
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January 2014
Research Article|
September 23 2013
Involvement of the HIF-1α and Wnt/β-catenin pathways in the protective effects of losartan on fatty liver graft with ischaemia/reperfusion injury
Ying-Ying Yang
;
Ying-Ying Yang
1
*Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
‡Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
Correspondence: Dr Ying-Ying Yang (email yyyang@vghtpe.gov.tw) or Professor Han-Chieh Lin (email hclin@vghtpe.gov.trw)
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Pei-Chang Lee
;
Pei-Chang Lee
†Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
‡Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
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Yi-Tsau Huang
;
Yi-Tsau Huang
‡Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
§National Research Institute of Chinese Medicine, Taipei, Taiwan
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Wei-Ping Lee
;
Wei-Ping Lee
†Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
‡Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
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Ying-Ju Kuo
;
Ying-Ju Kuo
‡Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
¶Department of Pathology, Taipei Veterans General Hospital, Taipei, Taiwan
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Kuei-Chuan Lee
;
Kuei-Chuan Lee
†Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
‡Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
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Yun-Cheng Hsieh
;
Yun-Cheng Hsieh
†Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
‡Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
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Tzung-Yan Lee
;
Tzung-Yan Lee
∥Graduate Institute of Traditional Chinese Medicine, Chang Gung University, Taipei, Taiwan
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Han-Chieh Lin
Han-Chieh Lin
1
†Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
‡Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
Correspondence: Dr Ying-Ying Yang (email yyyang@vghtpe.gov.tw) or Professor Han-Chieh Lin (email hclin@vghtpe.gov.trw)
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Clin Sci (Lond) (2014) 126 (2): 163–174.
Article history
Received:
January 14 2013
Revision Received:
June 11 2013
Accepted:
July 23 2013
Accepted Manuscript online:
July 23 2013
Citation
Ying-Ying Yang, Pei-Chang Lee, Yi-Tsau Huang, Wei-Ping Lee, Ying-Ju Kuo, Kuei-Chuan Lee, Yun-Cheng Hsieh, Tzung-Yan Lee, Han-Chieh Lin; Involvement of the HIF-1α and Wnt/β-catenin pathways in the protective effects of losartan on fatty liver graft with ischaemia/reperfusion injury. Clin Sci (Lond) 1 January 2014; 126 (2): 163–174. doi: https://doi.org/10.1042/CS20130025
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