Liver steatosis is associated with mitochondrial dysfunction and elevated reactive oxygen species (ROS) levels together with enhanced sensitivity to ischemia-reperfusion (IR) injury and limited response to preconditioning protocols. Here, we sought to determine whether the downregulation in the steatotic liver of peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α), a master regulator of mitochondrial metabolism and ROS that is known to play a role in liver metabolic control, could be responsible for the sensitivity of the steatotic liver to ischemic damage.
Results:
PGC-1α was induced in normal liver after exposure to an IR protocol, which was concomitant with an increase in the levels of antioxidant proteins. By contrast, its induction was severely blunted in the steatotic liver, resulting in a modest induction of antioxidant proteins. Livers of PGC-1α−/− mice on a chow diet were normal, but they exhibited an enhanced sensitivity to IR injury and also a lack of response to ischemic preconditioning (IPC), a phenotype that recapitulated the features of the steatotic liver in terms of liver damage, although the inflammatory response differed between both models. Utilizing an in vitro model of IPC, we found that PGC-1α expression was downregulated in hepatic cells cultured at 1% O2; whereas it was induced after reoxygenation (3% O2), and it was responsible for the recovery of antioxidant gene expression after the ischemic period.
Innovation & Conclusion:
PGC-1α plays an important role in the protection against IR injury in the liver, which is likely associated with its capacity to induce antioxidant gene expression. Antioxid. Redox Signal. 27, 1332–1346.
Get full access to this article
View all access options for this article.
References
1.
Aharoni-SimonM, Hann-ObercygerM, PenS, MadarZ, and TiroshO. Fatty liver is associated with impaired activity of PPARgamma-coactivator 1alpha (PGC1alpha) and mitochondrial biogenesis in mice. Lab Invest, 91: 1018–1028, 2011.
2.
AkhtarMZ, HendersonT, SutherlandA, VogelT, and FriendPJ. Novel approaches to preventing ischemia-reperfusion injury during liver transplantation. Transplant Proc, 45: 2083–2092, 2013.
3.
AranyZ, FooSY, MaY, RuasJL, Bommi-ReddyA, GirnunG, CooperM, LaznikD, ChinsomboonJ, RangwalaSM, BaekKH, RosenzweigA, and SpiegelmanBM. HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1alpha. Nature, 451: 1008–1012, 2008.
4.
BarrosoE, Rodriguez-CalvoR, Serrano-MarcoL, AstudilloAM, BalsindeJ, PalomerX, and Vazquez-CarreraM. The PPARbeta/delta activator GW501516 prevents the down-regulation of AMPK caused by a high-fat diet in liver and amplifies the PGC-1alpha-Lipin 1-PPARalpha pathway leading to increased fatty acid oxidation. Endocrinology, 152: 1848–1859, 2011.
5.
BejaouiM, PantaziE, Folch-PuyE, BaptistaPM, Garcia-GilA, AdamR, and Rosello-CatafauJ. Emerging concepts in liver graft preservation. World J Gastroenterol, 21: 396–407, 2015.
6.
BlighEG and DyerWJ. A rapid method of total lipid extraction and purification. Can J Biochem Physiol, 37: 911–917, 1959.
7.
BorniquelS, ValleI, CadenasS, LamasS, and MonsalveM. Nitric oxide regulates mitochondrial oxidative stress protection via the transcriptional coactivator PGC-1alpha. FASEB J, 20: 1889–1891, 2006.
8.
CantoC and AuwerxJ. PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Curr Opin Lipidol, 20: 98–105, 2009.
9.
CaraceniP, DomenicaliM, VendemialeG, GrattaglianoI, PertosaA, NardoB, Morselli-LabateAM, TrevisaniF, PalascianoG, AltomareE, and BernardiM. The reduced tolerance of rat fatty liver to ischemia reperfusion is associated with mitochondrial oxidative injury. J Surg Res, 124: 160–168, 2005.
10.
CarreauA, El Hafny-RahbiB, MatejukA, GrillonC, and KiedaC. Why is the partial oxygen pressure of human tissues a crucial parameter? Small molecules and hypoxia. J Cell Mol Med, 15: 1239–1253, 2011.
11.
CharltonM. Evolving aspects of liver transplantation for nonalcoholic steatohepatitis. Curr Opin Organ Transplant, 18: 251–258, 2013.
12.
ChenQ, MoghaddasS, HoppelCL, and LesnefskyEJ. Reversible blockade of electron transport during ischemia protects mitochondria and decreases myocardial injury following reperfusion. J Pharmacol Exp Ther, 319: 1405–1412, 2006.
13.
FeldsteinAE and BaileySM. Emerging role of redox dysregulation in alcoholic and nonalcoholic fatty liver disease. Antioxid Redox Signal, 15: 421–424, 2011.
14.
FulopP, DerdakZ, SheetsA, SaboE, BerthiaumeEP, ResnickMB, WandsJR, ParaghG, and BaffyG. Lack of UCP2 reduces Fas-mediated liver injury in ob/ob mice and reveals importance of cell-specific UCP2 expression. Hepatology, 44: 592–601, 2006.
15.
FunkJA and SchnellmannRG. Accelerated recovery of renal mitochondrial and tubule homeostasis with SIRT1/PGC-1alpha activation following ischemia-reperfusion injury. Toxicol Appl Pharmacol, 273: 345–354, 2013.
16.
GehrauRC, MasVR, DumurCI, SuhJL, SharmaAK, CathroHP, and MalufDG. Donor hepatic steatosis induce exacerbated ischemia-reperfusion injury through activation of innate immune response molecular pathways. Transplantation, 99: 2523–2533, 2015.
17.
GlanemannM, VollmarB, NusslerAK, SchaeferT, NeuhausP, and MengerMD. Ischemic preconditioning protects from hepatic ischemia/reperfusion-injury by preservation of microcirculation and mitochondrial redox-state. J Hepatol, 38: 59–66, 2003.
18.
GrangerDN and KvietysPR. Reperfusion injury and reactive oxygen species: the evolution of a concept. Redox Biol, 6: 524–551, 2015.
19.
GundewarS, CalvertJW, JhaS, Toedt-PingelI, JiSY, NunezD, RamachandranA, Anaya-CisnerosM, TianR, and LeferDJ. Activation of AMP-activated protein kinase by metformin improves left ventricular function and survival in heart failure. Circ Res, 104: 403–411, 2009.
20.
HanJS, WangHS, YanDM, WangZW, HanHG, ZhuHY, and LiXM. Myocardial ischaemic and diazoxide preconditioning both increase PGC-1alpha and reduce mitochondrial damage. Acta Cardiol, 65: 639–644, 2010.
21.
HarringTR, O'MahonyCA, and GossJA. Extended donors in liver transplantation. Clin Liver Dis, 15: 879–900, 2011.
22.
JiangY, ZhangH, DongLY, WangD, and AnW. Increased hepatic UCP2 expression in rats with nonalcoholic steatohepatitis is associated with upregulation of Sp1 binding to its motif within the proximal promoter region. J Cell Biochem, 105: 277–289, 2008.
23.
KevinLG, CamaraAK, RiessML, NovalijaE, and StoweDF. Ischemic preconditioning alters real-time measure of O2 radicals in intact hearts with ischemia and reperfusion. Am J Physiol Heart Circ Physiol, 284: H566–H574, 2003.
24.
KimJ, JangHS, and ParkKM. Reactive oxygen species generated by renal ischemia and reperfusion trigger protection against subsequent renal ischemia and reperfusion injury in mice. Am J Physiol Renal Physiol, 298: F158–F166, 2010.
25.
LebuffeG, SchumackerPT, ShaoZH, AndersonT, IwaseH, and Vanden HoekTL. ROS and NO trigger early preconditioning: relationship to mitochondrial KATP channel. Am J Physiol Heart Circ Physiol, 284: H299–H308, 2003.
26.
LuoY, ZhuW, JiaJ, ZhangC, and XuY. NMDA receptor dependent PGC-1alpha up-regulation protects the cortical neuron against oxygen-glucose deprivation/reperfusion injury. J Mol Neurosci, 39: 262–268, 2009.
27.
McCormackL, DutkowskiP, El-BadryAM, and ClavienPA. Liver transplantation using fatty livers: always feasible?. J Hepatol, 54: 1055–1062, 2011.
28.
MonsalveM, WuZ, AdelmantG, PuigserverP, FanM, and SpiegelmanBM. Direct coupling of transcription and mRNA processing through the thermogenic coactivator PGC-1. Mol Cell, 6: 307–316, 2000.
29.
OlmosY, ValleI, BorniquelS, TierrezA, SoriaE, LamasS, and MonsalveM. Mutual dependence of Foxo3a and PGC-1alpha in the induction of oxidative stress genes. J Biol Chem, 284: 14476–14484, 2009.
30.
PantaziE, BejaouiM, Folch-PuyE, AdamR, and Rosello-CatafauJ. Advances in treatment strategies for ischemia reperfusion injury. Expert Opin Pharmacother, 17: 169–179, 2016.
31.
PantaziE, Folch-PuyE, BejaouiM, PaniselloA, VarelaAT, RoloAP, PalmeiraCM, and Rosello-CatafauJ. PPARalpha agonist WY-14643 induces SIRT1 activity in rat fatty liver ischemia-reperfusion injury. Biomed Res Int, 2015: 894679, 2015.
32.
PattiME, ButteAJ, CrunkhornS, CusiK, BerriaR, KashyapS, MiyazakiY, KohaneI, CostelloM, SacconeR, LandakerEJ, GoldfineAB, MunE, DeFronzoR, FinlaysonJ, KahnCR, and MandarinoLJ. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: potential role of PGC1 and NRF1. Proc Natl Acad Sci U S A, 100: 8466–8471, 2003.
33.
PeraltaC, PeralesJC, BartronsR, MitchellC, GilgenkrantzH, XausC, PratsN, FernandezL, GelpiE, PanesJ, and Rosello-CatafauJ. The combination of ischemic preconditioning and liver Bcl-2 overexpression is a suitable strategy to prevent liver and lung damage after hepatic ischemia-reperfusion. Am J Pathol, 160: 2111–2122, 2002.
34.
PerlemuterG, Davit-SpraulA, CossonC, ContiM, BigorgneA, ParadisV, CorreMP, PratL, KuochV, BasdevantA, PelletierG, OppertJM, and BuffetC. Increase in liver antioxidant enzyme activities in non-alcoholic fatty liver disease. Liver Int, 25: 946–953, 2005.
35.
PratschkeS, AngeleMK, GrutznerU, TufmanA, BilzerM, LoeheF, JauchKW, and SchauerRJ. GSH attenuates organ injury and improves function after transplantation of fatty livers. Eur Surg Res, 45: 13–19, 2010.
36.
ReiniersMJ, van GolenRF, van GulikTM, and HegerM. Reactive oxygen and nitrogen species in steatotic hepatocytes: a molecular perspective on the pathophysiology of ischemia-reperfusion injury in the fatty liver. Antioxid Redox Signal, 21: 1119–1142, 2014.
37.
RouthD, NaiduS, SharmaS, RanjanP, and GodaraR. Changing pattern of donor selection criteria in deceased donor liver transplant: a review of literature. J Clin Exp Hepatol, 3: 337–346, 2013.
38.
Sanchez-RamosC, TierrezA, Fabregat-AndresO, WildB, Sanchez-CaboF, ArduiniA, DopazoA, and MonsalveM. PGC-1alpha regulates translocated in liposarcoma activity: role in oxidative stress gene expression. Antioxid Redox Signal, 15: 325–337, 2011.
39.
SempleRK, CrowleyVC, SewterCP, LaudesM, ChristodoulidesC, ConsidineRV, Vidal-PuigA, and O'RahillyS. Expression of the thermogenic nuclear hormone receptor coactivator PGC-1alpha is reduced in the adipose tissue of morbidly obese subjects. Int J Obes Relat Metab Disord, 28: 176–179, 2004.
40.
SolainiG and HarrisDA. Biochemical dysfunction in heart mitochondria exposed to ischaemia and reperfusion. Biochem J, 390: 377–394, 2005.
41.
SongX, XuH, FengY, LiX, LinM, and CaoL. Protective effect of grape seed proanthocyanidins against liver ischemic reperfusion injury: particularly in diet-induced obese mice. Int J Biol Sci, 8: 1345–1362, 2012.
42.
St-PierreJ, DroriS, UldryM, SilvaggiJM, RheeJ, JagerS, HandschinC, ZhengK, LinJ, YangW, SimonDK, BachooR, and SpiegelmanBM. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell, 127: 397–408, 2006.
43.
SummermatterS and HandschinC. PGC-1alpha and exercise in the control of body weight. Int J Obes (Lond), 36: 1428–1435, 2012.
44.
TashiroH, KurodaS, MikuriyaY, and OhdanH. Ischemia-reperfusion injury in patients with fatty liver and the clinical impact of steatotic liver on hepatic surgery. Surg Today, 44: 1611–1625, 2014.
45.
TiedeLM, CookEA, MorseyB, and FoxHS. Oxygen matters: tissue culture oxygen levels affect mitochondrial function and structure as well as responses to HIV viroproteins. Cell Death Dis, 2: e246, 2011.
46.
UchinoS, YamaguchiY, FuruhashiT, WangFS, ZhangJL, OkabeK, KiharaS, YamadaS, MoriK, and OgawaM. Steatotic liver allografts up-regulate UCP-2 expression and suffer necrosis in rats. J Surg Res, 120: 73–82, 2004.
47.
ValdecantosMP, PardoV, RuizL, Castro-SanchezL, LanzonB, Fernandez-MillanE, Garcia-MonzonC, ArrobaAI, Gonzalez-RodriguezA, EscrivaF, CarmenA, RuperezFJ, BarbasC, KonkarA, NaylorJ, HornigoldD, Dos SantosA, BednarekM, GrimsbyJ, RondinoneCM, and ValverdeAM. A novel glucagon-like peptide 1/glucagon receptor dual agonist improves steatohepatitis and liver regeneration in mice. Hepatology, 65: 950–968, 2016.
48.
ValleI, Alvarez-BarrientosA, ArzaE, LamasS, and MonsalveM. PGC-1alpha regulates the mitochondrial antioxidant defense system in vascular endothelial cells. Cardiovasc Res, 66: 562–573, 2005.
YangX, EnerbackS, and SmithU. Reduced expression of FOXC2 and brown adipogenic genes in human subjects with insulin resistance. Obes Res, 11: 1182–1191, 2003.
51.
ZhouW, ZhangY, HoschMS, LangA, ZwackaRM, and EngelhardtJF. Subcellular site of superoxide dismutase expression differentially controls AP-1 activity and injury in mouse liver following ischemia/reperfusion. Hepatology, 33: 902–914, 2001.
52.
ZwackaRM, ZhangY, ZhouW, HalldorsonJ, and EngelhardtJF. Ischemia/reperfusion injury in the liver of BALB/c mice activates AP-1 and nuclear factor kappaB independently of IkappaB degradation. Hepatology, 28: 1022–1030, 1998.
53.
ZweierJL and TalukderMA. The role of oxidants and free radicals in reperfusion injury. Cardiovasc Res, 70: 181–190, 2006.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
