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

Abstract

Significance: Hepatic ischemia-reperfusion (IR) injury results from the temporary deprivation of hepatic blood supply and is a common side effect of major liver surgery (i.e., transplantation or resection). IR injury, which in most severe cases culminates in acute liver failure, is particularly pronounced in livers that are affected by nonalcoholic fatty liver disease (NAFLD). In NAFLD, fat-laden hepatocytes are damaged by chronic oxidative/ nitrosative stress (ONS), a state that is acutely exacerbated during IR, leading to extensive parenchymal damage. Recent Advances: NAFLD triggers ONS via increased (extra)mitochondrial fatty acid oxidation and activation of the unfolded protein response. ONS is associated with widespread protein and lipid (per)oxidation, which reduces the hepatic antioxidative capacity and shifts the intracellular redox status toward an oxidized state. Moreover, activation of the transcription factor peroxisome proliferator-activated receptor a induces expression of mitochondrial uncoupling protein 2, resulting in depletion of cellular energy (ATP) reserves. The reduction in intracellular antioxidants and ATP in fatty livers consequently gives rise to severe ONS and necrotic cell death during IR. Critical Issues: Despite the fact that ONS mediates both NAFLD and IR injury, the interplay between the two conditions has never been described in detail. An integrative overview of the pathophysiology of NAFLD that renders steatotic hepatocytes more vulnerable to IR injury is therefore presented in the context of ONS. Future Directions: Effective methods should be devised to alleviate ONS and the consequences thereof in NAFLD before surgery in order to improve resilience of fatty livers to IR injury.

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

“…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.…”

Protective Mechanisms of Hypothermia in Liver Surgery and Transplantation

“…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).…”

“…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).…”

“…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).…”

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

“…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.…”