Reactive Oxygen and Nitrogen Species in Steatotic Hepatocytes: A Molecular Perspective on the Pathophysiology of Ischemia-Reperfusion Injury in the Fatty Liver

Reiniers, Megan J.; Golen, Rowan F. van; Gulik, Thomas M. van; Heger, Michal

doi:10.1089/ars.2013.5486

Cited by 108 publications

(104 citation statements)

References 236 publications

(282 reference statements)

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“…In this study, we indeed found increased ROS overproduction and oxidative stress in 10% fructose-fed rat livers and 5 mM fructose-exposed cultured hepatocytes, partly mediated by inhibition of Nrf2 transcriptional activity and the ROS-TXNIP signaling axis. Recently, more evidence demonstrates the importance of fructose in steatotic hepatocytes (43). These contradictory findings may be related to fructose concentration, its metabolism, and use of different experimental models.…”

Section: Figmentioning

confidence: 99%

Reactive Oxygen Species-Induced TXNIP Drives Fructose-Mediated Hepatic Inflammation and Lipid Accumulation Through NLRP3 Inflammasome Activation

Zhang

Chen

et al. 2015

Antioxidants & Redox Signaling

207

144

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Aims: Increased fructose consumption predisposes the liver to nonalcoholic fatty liver disease (NAFLD), but the mechanisms are elusive. Thioredoxin-interacting protein (TXNIP) links oxidative stress to NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation and this signaling axis may be involved in fructose-induced NAFLD. Here, we explore the role of reactive oxygen species (ROS)-induced TXNIP overexpression in fructose-mediated hepatic NLRP3 inflammasome activation, inflammation, and lipid accumulation. Results: Rats were fed a 10% fructose diet for 8 weeks and treated with allopurinol and quercetin during the last 4 weeks. Five millimolars of fructose-exposed hepatocytes (primary rat hepatocytes, rat hepatic parenchymal cells [RHPCs], HLO2, HepG2) were co-incubated with antioxidants or caspase-1 inhibitor or subjected to TXNIP or NLRP3 siRNA interference. Fructose induced NLRP3 inflammasome activation and proinflammatory cytokine secretion, janus-activated kinase 2/signal transducers and activators of transcription 3-mediated inflammatory signaling, and expression alteration of lipid metabolism-related genes in cultured hepatocytes and rat livers. NLRP3 silencing and caspase-1 suppression blocked these effects in primary rat hepatocytes and RHPCs, confirming that inflammasome activation alters hepatocyte lipid metabolism. Hepatocellular ROS and TXNIP were increased in animal and cell models. TXNIP silencing blocked NLRP3 inflammasome activation, inflammation, and lipid metabolism perturbations but not ROS induction in fructoseexposed hepatocytes, whereas antioxidants addition abrogated TXNIP induction and diminished the detrimental effects in fructose-exposed hepatocytes and rat livers. Innovation and Conclusions: This study provides a novel mechanism for fructose-induced NAFLD pathogenesis by which the ROS-TXNIP pathway mediates hepatocellular NLRP3 inflammasome activation, inflammation and lipid accumulation. Antioxidant-based interventions can inhibit the ROS-TXNIP pathway. Antioxid. Redox Signal. 22, 848-870.

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Section: Figmentioning

confidence: 99%

Reactive Oxygen Species-Induced TXNIP Drives Fructose-Mediated Hepatic Inflammation and Lipid Accumulation Through NLRP3 Inflammasome Activation

Zhang

Chen

et al. 2015

Antioxidants & Redox Signaling

207

144

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“…The mechanisms described under Ischemia and Mitochondrial Metabolites illustrate the pathways of ROS formation during hepatic I/R, which can compromise liver function during reperfusion by oxidizing proteins (33). Oxidative modification of amino acids in mitochondrial complex I, III and V has been observed in mouse livers subjected to I/R, leading to decreased ATP production during early reperfusion (34).…”

Section: Hypothermia and Immunomodulationmentioning

confidence: 99%

“…When ATP stores drop below these limits through the aforementioned mechanisms, the apoptotic process is redirected toward inactivation of hepatic insulin receptors by JNK (57). As stated in Hypothermia and Immunomodulation, JNK is activated by TNF-α and ROS during hepatic I/R injury (58), after which JNK initiates a positive feedback loop that enhances its own activation by upholding TNF-α and ROS formation (33). Both TNF-α and ROS, however, can also induce hepatocyte insulin resistance independently of JNK (57).…”

Section: Hypothermia and Immunomodulationmentioning

confidence: 99%

“…In addition to the JNK/AP-1 axis, the reduction in innate immune signaling after hypothermic I/R could also be mediated by nuclear factor (NF)-κB, which is a transcription factor that, depending on the cell type, can promote either cell death and inflammation or cell survival and proliferation (33,42). After 90 min of hypothermic (<29°C) ischemia in mice, NF-κB was increased in hepatocytes, but decreased in Kupffer cells (KCs) (45).…”

Section: Hypothermia and Glucose Metabolismmentioning

confidence: 99%

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Protective Mechanisms of Hypothermia in Liver Surgery and Transplantation

Olthof

Reiniers

Dirkes

et al. 2015

Mol Med

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Hepatic ischemia/reperfusion (I/R) injury is a side effect of major liver surgery that often cannot be avoided. Prolonged periods of ischemia put a metabolic strain on hepatocytes and limit the tolerable ischemia and preservation times during liver resection and transplantation, respectively. In both surgical settings, temporarily lowering the metabolic demand of the organ by reducing organ temperature effectively counteracts the negative consequences of an ischemic insult. Despite its routine use, the application of liver cooling is predicated on an incomplete understanding of the underlying protective mechanisms, which has limited a uniform and widespread implementation of liver-cooling techniques. This review therefore addresses how hypothermia-induced hypometabolism modulates hepatocyte metabolism during ischemia and thereby reduces hepatic I/R injury. The mechanisms underlying hypothermia-mediated reduction in energy expenditure during ischemia and the attenuation of mitochondrial production of reactive oxygen species during early reperfusion are described. It is further addressed how hypothermia suppresses the sterile hepatic I/R immune response and preserves the metabolic functionality of hepatocytes. Lastly, a summary of the clinical status quo of the use of liver cooling for liver resection and transplantation is provided.

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“…Intravascular sources of superoxide during I/R include xanthine oxidase and NADPH oxidase (NOX) in endothelial cells, leukocytes, and platelets [10], whereby NOX1 [26], NOX2 [27], and NOX4 [28] have been implicated in renal I/R. Although relatively innocuous itself, superoxide gives rise to more toxic secondary and tertiary reactive intermediates [29] that form from the superoxide dismutase-catalyzed end product hydrogen peroxide [30][31][32]. Superoxide also reacts with NO that is extensively produced during renal I/R [33] to form peroxynitrite [34,35], which oxidatively modifies proteins, DNA bases, and lipids by nitration, rendering the biomolecules dysfunctional.…”

Section: Introductionmentioning

confidence: 99%

TEMPOL has limited protective effects on renal oxygenation and hemodynamics but reduces kidney damage and inflammation in a rat model of renal ischemia/reperfusion by aortic clamping

Ergin

Bezemer

Kandil

et al. 2015

JCTRes

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Background: Renal ischemia-reperfusion (I/R) is a common clinical complication in critically ill patients that is associated with considerable morbidity and mortality. Renal I/R is a major cause of acute kidney injury (AKI) resulting from I/R-induced oxidative stress, sterile inflammation, and microcirculatory perfusion defects, which can be ameliorated with the superoxide scavenger TEMPOL. The most common cause of AKI in the clinical setting is aortic surgery with suprarenal aortic clamping. The protective effect of TEMPOL in aortic clamping-induced renal I/R has not been studied before. Aim: To evaluate the protective effects of TEMPOL on oxidative stress, inflammation, tissue injury, and renal hemodynamics and oxygenation in a clinically representative rat model of I/R using aortic crossclamping. Methods: Animals (N = 24) were either sham-operated or subjected to ischemia (30 min) and 90-min reperfusion, with or without TEMPOL treatment (15 min before ischemia and during entire reperfusion phase, 200 μmol/kg/h). Systemic and renal hemodynamics, renal oxygenation, and blood gas values were determined at 15 min and 90 min of reperfusion. At 90-min reperfusion, iNOS, inflammation (IL-6, MPO), oxidative stress (MDA), and tissue damage (NGAL, L-FABP) were determined in tissue biopsies. Results: TEMPOL administration at a cumulative dose of 400 μmol/kg conferred a protective effect on AKI in terms of reducing renal damage, inflammation, and iNOS activation. With respect to renal hemodynamics and oxygenation, TEMPOL only reduced renal vascular resistance to near-baseline levels at both reperfusion time points and partially ameliorated the I/R-induced drop microvascular partial tension of oxygen at 90 min reperfusion. Also, TEMPOL alleviated the I/R-induced metabolic acidosis. However, TEMPOL exerted no restorative effect in terms of the severely reduced mean arterial pressure, renal blood flow, and renal oxygen delivery and consumption. The renal oxygen extraction ratio remained unchanged during the 90-min reperfusion phase. Kidneys in all groups were anuric throughout the experiment. Conclusions: This clinically representative renal I/R model, which entails both renal I/R and hind limb I/R as opposed to the standardly used renal I/R model that employs renal artery clamping, resulted in relatively moderate direct AKI. The damage was exacerbated by the perturbed systemic hemodynamics and metabolic acidosis as a result of the hind limb I/R. TEMPOL partially intervened in the factors that led to AKI as well as renal microvascular partial tension of oxygen and metabolic acidosis. However, more effective interventions should be devised for the mean arterial pressure drop (i.e., anuria) associated with aortic clamping and for restoring other critical renal hemodynamic and oxygenation parameters in order to improve post-I/R renal function. Relevance for patients: TEMPOL is a promising compound that has been shown to protect kidneys from I/R damage, which is relevant in kidney transplantation, pancreas transplantation, and ...

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Reactive Oxygen and Nitrogen Species in Steatotic Hepatocytes: A Molecular Perspective on the Pathophysiology of Ischemia-Reperfusion Injury in the Fatty Liver

Cited by 108 publications

References 236 publications

Reactive Oxygen Species-Induced TXNIP Drives Fructose-Mediated Hepatic Inflammation and Lipid Accumulation Through NLRP3 Inflammasome Activation

Reactive Oxygen Species-Induced TXNIP Drives Fructose-Mediated Hepatic Inflammation and Lipid Accumulation Through NLRP3 Inflammasome Activation

Protective Mechanisms of Hypothermia in Liver Surgery and Transplantation

TEMPOL has limited protective effects on renal oxygenation and hemodynamics but reduces kidney damage and inflammation in a rat model of renal ischemia/reperfusion by aortic clamping

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