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Oxidative Stress and Redox Signaling in the Pathophysiology of Liver Diseases

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The increased production of derivatives of molecular oxygen and nitrogen in the form of reactive oxygen species (ROS) and reactive nitrogen species (RNS) lead to molecular damage called oxidative stress. Under normal physiological conditions, the ROS generation is tightly regulated in different cells and cellular compartments. Any disturbance in the balance between the cellular generation of ROS and antioxidant balance leads to oxidative stress. In this article, we discuss the sources of ROS (endogenous and exogenous) and antioxidant mechanisms. We also focus on the pathophysiological significance of oxidative stress in various cell types of the liver. Oxidative stress is implicated in the development and progression of various liver diseases. We narrate the master regulators of ROS‐mediated signaling and their contribution to liver diseases. Nonalcoholic fatty liver diseases (NAFLD) are influenced by a “multiple parallel‐hit model” in which oxidative stress plays a central role. We highlight the recent findings on the role of oxidative stress in the spectrum of NAFLD, including fibrosis and liver cancer. Finally, we provide a brief overview of oxidative stress biomarkers and their therapeutic applications in various liver‐related disorders. Overall, the article sheds light on the significance of oxidative stress in the pathophysiology of the liver. © 2022 American Physiological Society. Compr Physiol 12:3167‐3192, 2022.

Figure 1. Figure 1. Mechanisms of generation of ROS‐mediated oxidative stress in the liver. Increased lipid accumulation in hepatocytes via fatty acid uptake and de novo lipogenesis using several lipogenic enzymes augments mitochondrial β‐oxidation leading to incessant generation of ROS. Hepatic nonparenchymal cells are also involved in ROS generation by activating the toll‐like receptors (TLRs) on the Kupffer cells and HSCs. In Kupffer cells, TLR4 in response to SFA and TLR1/2/6 for FFA activation triggers NOX‐2‐mediated ROS generation, resulting in oxidative stress. In HSCs, accumulation of cholesterol and acetyl‐CoA generates huge amount of ROS through glucose metabolism.
Figure 2. Figure 2. Putative sources of ROS and their contribution to pathologies of liver diseases. Under physiological conditions, organelle systems generate steady‐state ROS levels that promote redox signaling. On the other hand, under pathological conditions, excess ROS produced various danger signals such as DAMPS and ATP from the mitochondria and unfolded/misfolded proteins from the ER and oncogenes that promote mitochondrial dysfunction, ER stress, and DNA damage. All these factors lead to the development of liver pathologies such as inflammation, fibrosis, and even cancer.
Figure 3. Figure 3. Master regulators of oxidative stress response leading to inflammation and insulin resistance: Oxidative stress causes severe DNA damage sensed by p53 accumulation. Oxidative stress exerts its effects through the ER and mitochondrial stress (complete events mentioned in the review). NRF2 is the cumulative stress response marker induced by the ER and mitochondrial stress. ER stress‐induced inflammation is mediated by the recently discovered HMGB1 transcription factor, which further intersects with RAGE signaling. C‐GAS/STING pathway is the intracellular DNA‐sensing pathway activated by the mitochondrial DNA leaked into the cytosol. NLRP3 is either directly activated by TRPM2 or could be upstream of C‐GAS/STING pathway. Thus, NLRP3 co‐operates with C‐GAS/STING pathway to promote inflammation and insulin resistance.
Figure 4. Figure 4. The mechanisms of ROS‐induced oxidative stress in the pathogenesis of NAFLD. ROS can oxidize stored lipids through the process of lipid peroxidation, releasing lipid peroxidation reactive aldehydes, which result in lipotoxicity. Lipotoxicity involves in the production of several hepatic inflammatory mediators. ROS also increases the production of danger signals and mtDNA stimulating the innate immune system and inflammatory cytokines to promote liver inflammation. ROS‐associated lipid peroxidation and cytokines contribute to the inflammatory cell infiltrate. On the other hand, ROS‐mediated oxidative stress is a feature of liver fibrosis that activates HSCs by releasing several profibrotic stimuli and growth factors such as TGF‐β, leptin, AGEs, and PDGF. Further, ROS induces DNA damage, resulting in cancer cell transformation.

Figure 1. Mechanisms of generation of ROS‐mediated oxidative stress in the liver. Increased lipid accumulation in hepatocytes via fatty acid uptake and de novo lipogenesis using several lipogenic enzymes augments mitochondrial β‐oxidation leading to incessant generation of ROS. Hepatic nonparenchymal cells are also involved in ROS generation by activating the toll‐like receptors (TLRs) on the Kupffer cells and HSCs. In Kupffer cells, TLR4 in response to SFA and TLR1/2/6 for FFA activation triggers NOX‐2‐mediated ROS generation, resulting in oxidative stress. In HSCs, accumulation of cholesterol and acetyl‐CoA generates huge amount of ROS through glucose metabolism.

Figure 2. Putative sources of ROS and their contribution to pathologies of liver diseases. Under physiological conditions, organelle systems generate steady‐state ROS levels that promote redox signaling. On the other hand, under pathological conditions, excess ROS produced various danger signals such as DAMPS and ATP from the mitochondria and unfolded/misfolded proteins from the ER and oncogenes that promote mitochondrial dysfunction, ER stress, and DNA damage. All these factors lead to the development of liver pathologies such as inflammation, fibrosis, and even cancer.

Figure 3. Master regulators of oxidative stress response leading to inflammation and insulin resistance: Oxidative stress causes severe DNA damage sensed by p53 accumulation. Oxidative stress exerts its effects through the ER and mitochondrial stress (complete events mentioned in the review). NRF2 is the cumulative stress response marker induced by the ER and mitochondrial stress. ER stress‐induced inflammation is mediated by the recently discovered HMGB1 transcription factor, which further intersects with RAGE signaling. C‐GAS/STING pathway is the intracellular DNA‐sensing pathway activated by the mitochondrial DNA leaked into the cytosol. NLRP3 is either directly activated by TRPM2 or could be upstream of C‐GAS/STING pathway. Thus, NLRP3 co‐operates with C‐GAS/STING pathway to promote inflammation and insulin resistance.

Figure 4. The mechanisms of ROS‐induced oxidative stress in the pathogenesis of NAFLD. ROS can oxidize stored lipids through the process of lipid peroxidation, releasing lipid peroxidation reactive aldehydes, which result in lipotoxicity. Lipotoxicity involves in the production of several hepatic inflammatory mediators. ROS also increases the production of danger signals and mtDNA stimulating the innate immune system and inflammatory cytokines to promote liver inflammation. ROS‐associated lipid peroxidation and cytokines contribute to the inflammatory cell infiltrate. On the other hand, ROS‐mediated oxidative stress is a feature of liver fibrosis that activates HSCs by releasing several profibrotic stimuli and growth factors such as TGF‐β, leptin, AGEs, and PDGF. Further, ROS induces DNA damage, resulting in cancer cell transformation.
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Raja Gopal Reddy Mooli, Dhanunjay Mukhi, Sadeesh K. Ramakrishnan. Oxidative Stress and Redox Signaling in the Pathophysiology of Liver Diseases. Compr Physiol 2022, 12: 3167-3192. doi: 10.1002/cphy.c200021