title: Involvement of the HIF-1α and Wnt/β-catenin pathways in the protective effects of losartan on fatty liver graft with ischaemia/reperfusion injury.
abstract: 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.
authors.affiliation: ∥Graduate Institute of Traditional Chinese Medicine, Chang Gung University, Taipei, Taiwan.
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Yang
authors.forename: Pei-Chang
authors.initials: PC
authors.lastname: Lee
authors.forename: Yi-Tsau
authors.initials: YT
authors.lastname: Huang
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Lee
authors.forename: Ying-Ju
authors.initials: YJ
authors.lastname: Kuo
authors.forename: Kuei-Chuan
authors.initials: KC
authors.lastname: Lee
authors.forename: Yun-Cheng
authors.initials: YC
authors.lastname: Hsieh
authors.forename: Tzung-Yan
authors.initials: TY
authors.lastname: Lee
authors.forename: Han-Chieh
authors.initials: HC
authors.lastname: Lin
mesh_terms: D000818:Animals; D059305:Diet, High-Fat; D005234:Fatty Liver / Q000503:physiopathology*; D006023:Glycoproteins / Q000494:pharmacology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D065626:Non-alcoholic Fatty Liver Disease; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000517:prevention & control*; D015398:Signal Transduction / Q000502:physiology*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D015854:Up-Regulation; D060449:Wnt Signaling Pathway / Q000502:physiology*; D060509:Wnt3A Protein / Q000494:pharmacology; D051176:beta Catenin / Q000502:physiology*; D000099274:Frizzled-Related Proteins
chemical_list: D006023:Glycoproteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; D019808:Losartan; D017392:Thiobarbituric Acid Reactive Substances; D060509:Wnt3A Protein; D051176:beta Catenin; D000099274:Frizzled-Related Proteins; C555511:Wnt3a protein, mouse