4. The Impact of Oxidative Stress on Liver Cells
The liver is continuously exposed to different toxic and reactive metabolites including ROS and RNS. A shift in the redox balance toward oxidative stress can be considered an initial step in the pathogenesis of liver diseases
[38]. This process is affected by comorbidities such as diabetes/insulin resistance and by various exogenous factors such as alcohol abuse, viral infection, drug overdose, high-caloric diet, and exposure to environmental toxins, UV light or heavy metals. A surge in ROS and RNS levels is important in the onset of inflammatory reactions, fibrosis, necrosis, apoptosis or malignant transformation
[28][38][28,38].
Hepatocytes are important sites of ROS production, especially in mitochondria, and are also sensitive to ROS-mediated injury. Each hepatocyte contains 1000 to 2000 mitochondria occupying about 20% of the cell volume
[39]. ROS-mediated damage of lipids and particularly, PUFAs, can alter cell membrane fluidity and permeability. Mitochondrial lipid peroxidation negatively affects the electron transport chain, aggravating ROS production and oxidative stress
[38]. Mitochondrial dysfunction in hepatocytes has been linked to the development and progression of chronic liver disorders
[38][40][38,40]. For instance, patients with non-alcoholic steatohepatitis (NASH) exhibit hepatic oxidative stress due to impaired mitochondrial respiratory capacity and proton leakage
[41]. In a mouse model of fatty liver disease, pharmacological improvement of mitochondrial redox homeostasis with the flavonoid dihydromyricetin was shown to be hepatoprotective
[42]. Hjv
−/− mice, a model of hereditary iron overload (hemochromatosis), exhibit mitochondrial hyperactivity in hepatocytes, which predisposes them to HCC
[43]. On the other hand, pharmacological chelation of mitochondrial iron has been shown to promote mitophagy, which protects mice against HCC
[44]. Experiments with primary rat hepatocytes and rat H4IIEC3 hepatoma cells showed that palmitate treatment promotes a flux of calcium from ER to mitochondria, which causes mitochondrial oxidative stress and lipotoxicity. These data highlight the physiological importance of finetuning mitochondrial activities and redox balance. Accumulation of ROS can induce hepatocellular dysfunction or death that will eventually result in the release of damage-associated molecular patterns (DAMPs). Under these circumstances, non-parenchymal cells, such as KCs, HSCs and newly recruited immune cells are activated and produce pro-fibrogenic and pro-inflammatory mediators
[45].
Oxidative stress promotes an influx of calcium into cells and redistribution of cellular calcium from the endoplasmic reticulum (ER) to the cytosol, mitochondria and nuclei, which in turn may trigger apoptotic and necrotic death
[46]. These responses increase mitochondrial permeability transition and facilitate the release of pro-apoptotic factors such as cytochrome c, and the activation of calcium-dependent endonucleases, proteases and lipases, contributing to the death of hepatocytes and other liver cell types
[47]. In addition, oxidative stress can affect the secretory functions of hepatocytes by disrupting the formation of bile flow, leading to cholestasis
[48].
While ROS and lipid peroxidation products impair hepatocellular function and viability, they promote the differentiation and activation of HSCs to myofibroblasts, leading to the secretion and accumulation of collagen and other ECM components within the liver
[49]. Therefore, chronic activation of HSCs in response to oxidative stress favors the development of liver fibrosis, which may progress to cirrhosis and HCC
[50][51][50,51].
KCs are also activated by certain stimulants leading to ROS production, expression of a variety of cytokines and pro-inflammatory mediators, and recruitment of more immune cells
[52]. Experimental studies with animal models have shown that ROS originating from KCs play a prominent role in the development of liver injury in response to hepatotoxins
[53][54][55][53,54,55]. KCs secrete transforming growth factor β (TGF-β) and platelet-derived growth factor (PDGF), which in turn promote HSC activation, contributing to liver fibrosis
[52]. In addition, KCs can directly kill hepatocytes through the activation of Fas-dependent apoptosis
[56].
LSECs are sensitive to oxidative stress mainly due to their low H
2O
2 clearance capacity
[57][58][57,58], but also due to their exposure to gut-derived toxins carried in the portal vein
[59]. Therefore, ROS can selectively damage LSECs and impair their physiological activities. For instance, the oxidation of spectrin can disrupt its interaction with actin, which is essential to maintain fenestrae structure and function, and thereby cause fenestrae closure
[60]. Defenestration impairs the bidirectional exchange of molecules between hepatocytes and hepatic blood sinuses
[61]. Vascular endothelial dysfunction driven by oxidative stress and inflammation plays an important role in liver injury
[62][63][64][62,63,64]. Thus, it may lead to the decreased generation of vasodilator factors such as NO and promote vasoconstriction, which causes increased resistance in sinusoidal microcirculation and portal hypertension
[65].
Autophagy is the main endogenous recycling process that preserves cell homeostasis under physiological conditions and offers a survival mechanism under stress
[66]. Experimental studies with animal models suggest that autophagy protects LSECs against oxidative stress responses to acute liver injury, while impairment of this pathway leads to endothelial dysfunction and contributes to HSC activation and liver fibrosis
[62]. Along these lines, NASH patients exhibit smaller autophagic vacuoles in LSECs
[67], indicating that autophagy is dysregulated in liver diseases.
Cholangiocytes are involved in cholangiopathies, which can be mediated by oxidative stress factors
[48]. Nevertheless, the effects of oxidative stress on cholangiocyte pathophysiology are not well understood. As an example, increased oxidative stress can induce senescence in cholangiocytes through the stimulation of ER stress
[68]. On the other hand, melatonin appears to protect cholangiocytes against oxidative stress-induced cell damage and inflammation
[69].
NK cells are generally susceptible to ROS, and oxidative stress can alter their activity. This can contribute to immune escape within the tumor microenvironment
[70][71][70,71]. However, the role of oxidative stress on liver resident NK cells (Pit cells) in the context of liver disease is not clear. The effects of oxidative stress on the various liver cell types are schematically illustrated in
Figure 3.
Figure 3. Effects of oxidative stress on different liver cells.