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Finelli, C. Mediators of Hepatotoxicity from Excess of Lipids. Encyclopedia. Available online: https://encyclopedia.pub/entry/45603 (accessed on 27 July 2024).
Finelli C. Mediators of Hepatotoxicity from Excess of Lipids. Encyclopedia. Available at: https://encyclopedia.pub/entry/45603. Accessed July 27, 2024.
Finelli, Carmine. "Mediators of Hepatotoxicity from Excess of Lipids" Encyclopedia, https://encyclopedia.pub/entry/45603 (accessed July 27, 2024).
Finelli, C. (2023, June 15). Mediators of Hepatotoxicity from Excess of Lipids. In Encyclopedia. https://encyclopedia.pub/entry/45603
Finelli, Carmine. "Mediators of Hepatotoxicity from Excess of Lipids." Encyclopedia. Web. 15 June, 2023.
Mediators of Hepatotoxicity from Excess of Lipids
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This entry is adapted from the peer-reviewed paper 10.3390/gidisord5020020

Non-alcoholic fatty liver disease (NAFLD) is currently the leading cause of chronic liver disease in Western countries; the molecular mechanisms leading to NAFLD are only partially understood and there are no effective therapeutic interventions. The prevalence of liver disease is constantly increasing in industrialized countries due to a number of lifestyle variables, including excessive caloric intake, unbalanced diet, lack of physical activity, and abuse of hepatotoxic medicines. 

mediators of hepatotoxicity lipids hepatic statosis toll-like receptors

1. Introduction

It has been shown that hepatic steatosis, formerly thought to be the start of non-alcoholic fatty liver disease (NAFLD), is actually a healthy increase in triglycerides, whereas free fatty acids are the toxic molecules that lead to steatohepatitis and fibrosis [1][2]. In a mouse model, genetic suppression of the enzyme diacylglycerol acyltransferase 2 (DGAT2) decreased hepatic steatosis while increasing fibrosis due to the toxic effects of FFAs [3]. Lipotoxicity mediated by FFAs (cellular toxicity caused by fat accumulation) in liver cells may originate from the disruption of triglyceride synthesis [4].
NAFLD is a group of diseases that include cirrhosis, steatosis, and steatohepatitis, which are characterized by fatty infiltration of the liver. NAFLD is the most common liver disease, with an estimated prevalence worldwide of around 25% [5]. The current epidemic of obesity and metabolic syndrome, which manifest in the liver as NAFLD, may be responsible for the sudden increase in the incidence of NAFLD [6]. The majority of patients with NAFLD have simple hepatic steatosis without steatohepatitis and fibrosis. In addition, in 2–3% of individuals, NAFLD can become non-alcoholic steatohepatitis (NASH), which can lead to progressive fibrosis, cirrhosis, and consequences such as hepatocellular carcinoma [7][8][9]. As much as 50% of patients with simple steatosis who later develop NASH may also develop severe fibrosis [10].
The parenchyma of the liver is made up of a variety of cell types, the bulk of which are hepatocytes (around 70% of the liver cell population) [11]. Parenchymal cells include hepatocytes and cholangiocytes, while nonparenchymal cells consist of Kupffer cells, stellate cells, and endothelial cells. Hepatic cells orchestrate the development of liver disorders. Hepatocytes, macrophages, and hepatic stellate cells interact in NAFLD and its severe variant, non-alcoholic steatohepatitis (NASH), although the precise methods through which these cells are orchestrated are not fully understood [11][12].
Patients with NAFLD have higher levels of oleic acid, a monounsaturated fatty acid (MUFA), and palmitic acid, according to studies examining the makeup of hepatic and circulatory free fatty acids (a saturated fatty acid (SFA)) [13][14]. However, polyunsaturated fatty acids have not been demonstrated to be toxic to hepatocytes and may even be beneficial in NAFLD patients [15][16]. Experimental research on this subject in human B cells has examined the function of stearoyl-CoA desaturase-1 (SCD1), the enzyme that changes SFA into MUFA [17]. More MUFAs are produced because of the increased expression of SCD1, and these MUFAs are then incorporated into triglycerides to produce simple and well-tolerated hepatic steatosis [18]. However, the removal of SCD1 results in the accumulation of SFA, which in turn triggers hepatocyte death and steatohepatitis [19]. Therefore, the type of FFAs stored in hepatocytes is just as important for developing NAFLD as the amount of FFAs accumulated, if not more [20]. Apoptosis, a form of programmed cellular death, is considered a key mechanism in developing NAFLD [21][22]. The main pathogenic mechanism seen in the biopsy samples of NASH patients is apoptosis, and in the spectrum of NAFLD, the presence of apoptosis helps to identify NASH patients from those with simple steatosis [23]. Patients who have higher levels of apoptosis will have advanced fibrosis because the degree of apoptosis and inflammation are inversely correlated [24]. The correlation between the levels of circulating cytokeratin-18 fragments, which are indicators of apoptotic liver cells, and the degree of fibrosis, provides additional evidence that apoptosis plays a significant role in NASH [25]. Lipoapoptosis is the name given to apoptosis mediated by FFAs [26]. Activation of the apoptotic pathways may occur either by an extrinsic pathway mediated by cell surface receptors or by an intrinsically mediated pathway by intracellular organelles [27].
A fundamental component of NASH is the lipotoxicity of hepatocytes. Lipotoxicity is caused by the accumulation of lipid intermediates, which cause cell malfunction and cell death. In NASH, hepatocytes build up triglycerides and various lipid metabolites, including free cholesterol, ceramides, and free fatty acids (FFA) [28]. Hepatocytes store most fatty acids as triglycerides, and some data suggest that the esterification of fatty acids into neutral triglycerides provides a protection mechanism against lipotoxicity [4][29]. On the other hand, FFA causes liver damage and activates specific signaling stunts, resulting in hepatocytic apoptosis, which in this context is called lipoapoptosis [30]. FFA is thus regarded as a major mediator of the lipotoxicity of hepatocytes. In fact, in NASH, there is an increased hepatic inflow of FFA following increased lipolysis in the peripheral fat tissue due to insulin resistance [31]. The lipotoxicity of FFA in hepatocytes is partially mediated through their intracellular lysophosphatidyl choline metabolite, which has also been seen to increase in the liver of patients with NAFLD in proportion with the severity of the disease [29].
Antihyperlipidemic drugs frequently cause mixed hepatocellular or liver lesions, with rare cases of pure cholestatic image [32][33]. The cytochrome P450 system, bile acid transport protein dysfunction, immune-mediated inflammatory response to the drug or its metabolites, immune-mediated apoptosis by tumor necrosis factor, and oxidative stress as a result of intracellular damage are some of the various proposed mechanisms of hepatotoxicity that vary depending on the drug or drug class [34].

2. Mediators of Hepatotoxicity from Excess of Lipids

2.1. Toll-like Receptors

Toll-like receptors (TLRs) are pattern recognition receptors that are able to detect molecular forms associated with pathogens, and, as a result, they can activate the immune system by means of pro-inflammatory signaling pathways [35]. The production of adipocytokines such as TNF-α and IL-6 is high when TLR4-mediated upregulation of NF-κB is activated by saturated fatty acids such as palmitic acid [36]. A reduction in the expression of TLR4 in mutating mice has been shown to be protective against the development of NASH [37]. Mice that received high-fat diet and dextran sulfate sodium (DSS) had high levels of bacterial lipopolysaccharides in the portal circulation, a higher expression of TLR4, and severe liver inflammation when compared with the controls [38]. TLR4 may be the key component of the gut microbiota−liver axis, which influences the development of NASH [39]. In fact, TLR4 stimulation can stimulate the production of ROS by hepatic macrophages and improve the expression of pro-interleukin-1, eventually promoting the development of NASH [40]. This demonstrates how the etiology of NASH is affected by the impact of gut microbiota dysbiosis-mediated LPS/TLR4 activation.

2.2. Death Receptors

Death receptors, which are receptor family tumor necrosis factors on the cellular surface, are essential in extrinsic apoptotic pathways [41]. The liver expresses several death receptors and their ligands, including tumor necrosis factor receptor 1 (TNF-R1), TNF related apoptosis-inducing ligand receptor 1 and 2 (TRAILR1 and TRAIL-R2), Fas ligand (FasL), TNF-α, and TRAIL [42]. The death ligands in the extrinsic pathway bind their receptors to create a death complex, which then activates caspase-8 to cause apoptosis (caspases are proteolytic enzymes causing death) [43]. An essential characteristic of NASH is the over-expression of these death receptors and the resulting apoptosis [44].

2.3. Mitochondrial Dysfunction and Reactive Oxygen Species

Cell damage due to reactive oxygen species (ROS), a class of free radicals generated from molecular oxygen, is called “oxidative stress” [45]. Although the mitochondria are a major source of ROS and are generated by oxidative reactions within cells, levels of ROS are very low in healthy cells due to a variety of antioxidant defensive mechanisms [46][47]. The liver prefers to eliminate FFAs through mitochondrial β-oxidation in healthy individuals [48]. However, in NAFLD, there is an excess of FFAs, and the increase in mitochondrial β-oxidation translates into an increase in electron supply at the electron transport chain; this causes the electron transport chain to be over reduced and ROS to develop [49]. Given that mitochondrial DNA is likely to be damaged by ROS, a higher production of ROS results in mitochondrial malfunction, increasing the risk of ROS formation [50]. The release of proapoptotic proteins such as cytochrome c into the cytosol is produced by mitochondrial dysfunction caused by intracellular stress caused by an accumulation of ROS [51]. Apoptosome is an active complex formed when cytochrome c, apoptotic-protein activation factor-1 (Apaf-1), and caspase 9 attach [52]. Caspases 3, 6, and 7 downstream are activated by apoptosome to achieve the remaining stages of apoptosis [53].

2.4. Lysosomal Permeabilization

The investigation of molecular mechanisms makes it possible to discover the lysosomal−mitochondrial axis in FFA-induced lipotoxicity and the potential role of lysosomic permeability in the progression of NASH [54]. Mitochondrial dysfunction is considered to be the principal pathophysiologic process contributing to the progression of NALFD into NASH [55]. In human liver cells, lysosomal permeabilization and the release of the lysosomal protease cathepsin B occurred far earlier than mitochondrial dysfunction and cytochrome c release into the cytosol [56]. In addition, the inhibition of cathepsine B protects against lipotoxicity caused by FFA [4]. By activating hepatic stellate cells and promoting their development in the myofibroblasts of mice, cathepsin B is also related to the evolution of hepatic fibrosis [57].

2.5. Endoplasmic Reticulum Stress

An intracellular organelle called the endoplasmic reticulum (ER) carries out many critical tasks such as protein and lipid production [58]. When the ER is stressed (ER stress), it responds with a process known as an unfolded protein response (UPR) [59]. UPR aims to protect ER from stress caused by a number of factors, including viral infections, alcohol, and FFAs [60]. However, if stress in the ER goes on for a long time, UPR might be unable to handle it, causing apoptosis [61]. In vitro research, using different models of exocrine pancreas cells, has shown how saturated fatty acid, such as palmitic acid, could produce ER stress and hepatic cell death, furthering our understanding of the role of ER stress [62]. Apoptosis can also to be caused by FFAs in other ways, including mitochondrial dysfunction caused by the activation of c-Jun N-terminal kinase (JNK), mitochondrial permeabilization caused by the pro-apoptotic protein BAX, free cholesterol-mediated ER stress, and ceramide-mediated apoptosis induced by death ligands such as TNF and FAS [63] (Figure 1).
Gastrointestdisord 05 00020 g001 550
Figure 1. Possible mechanisms through which FFAs can lead to apoptosis. Lysosomal permeabilization, ER stress, and mitochondrial malfunction are all associated with the activation of the mitochondrial route of apoptosis. FFA may also upregulate and increase the amount of death receptors in the plasma membrane, such as Fas and TRAIL receptor 5 (DR5). These harmful fatty acids may also stimulate TLR4 signaling, which will increase the production of a number of cytokines that promote inflammation. Moreover, other lipid forms including ceramide and free cholesterol (FC) may cause mitochondrial malfunction and trigger the apoptotic pathway in the mitochondria. Abbreviations: SFA: saturated fatty acids; FC: free cholesterol; CE: cholesteryl-ester; ER: endoplasmic reticulum.

References

  1. Tarantino, G.; Finelli, C. Pathogenesis of hepatic steatosis: The link between hypercortisolism and non-alcoholic fatty liver disease. World J. Gastroenterol. 2013, 19, 6735–6743.
  2. Cui, K.; Zhang, L.; La, X.; Wu, H.; Yang, R.; Li, H.; Li, Z. Ferulic Acid and P-Coumaric Acid Synergistically Attenuate Non-Alcoholic Fatty Liver Disease through HDAC1/PPARG-Mediated Free Fatty Acid Uptake. Int. J. Mol. Sci. 2022, 23, 15297.
  3. Gluchowski, N.L.; Gabriel, K.R.; Chitraju, C.; Bronson, R.T.; Mejhert, N.; Boland, S.; Wang, K.; Lai, Z.W. Hepatocyte Deletion of Triglyceride-Synthesis Enzyme Acyl CoA: Diacylglycerol Acyltransferase 2 Reduces Steatosis Without Increasing Inflammation or Fibrosis in Mice. Hepatology 2019, 70, 1972–1985.
  4. Lipke, K.; Kubis-Kubiak, A.; Piwowar, A. Molecular Mechanism of Lipotoxicity as an Interesting Aspect in the Development of Pathological States—Current View of Knowledge. Cells 2022, 11, 844.
  5. Cotter, T.G.; Rinella, M. Nonalcoholic Fatty Liver Disease 2020: The State of the Disease. Gastroenterology 2020, 158, 1851–1864.
  6. Godoy-Matos, A.F.; Júnior, W.S.S.; Valerio, C.M. NAFLD as a continuum: From obesity to metabolic syndrome and diabetes. Diabetol. Metab. Syndr. 2020, 12, 60.
  7. Finelli, C.; Tarantino, G. What is the role of adiponectin in obesity related non-alcoholic fatty liver disease? World J. Gastroenterol. 2013, 19, 802–812.
  8. Paul, S.; Dhamija, E.; Kedia, S. Non-alcoholic fatty liver disease associated with hepatocellular carcinoma: An increasing concern. Indian J. Med. Res. 2019, 149, 9–17.
  9. Ramai, D.; Facciorusso, A.; Vigandt, E.; Schaf, B.; Saadedeen, W.; Chauhan, A.; di Nunzio, S.; Shah, A.; Giacomelli, L.; Sacco, R. Progressive Liver Fibrosis in Non-Alcoholic Fatty Liver Disease. Cells 2021, 10, 3401.
  10. Mazzolini, G.; Sowa, J.-P.; Atorrasagasti, C.; Kücükoglu, Ö.; Syn, W.-K.; Canbay, A. Significance of Simple Steatosis: An Update on the Clinical and Molecular Evidence. Cells 2020, 9, 2458.
  11. Sato, K.; Kennedy, L.; Liangpunsakul, S.; Kusumanchi, P.; Yang, Z.; Meng, F.; Glaser, S.; Francis, H.; Alpini, G. Intercellular Communication between Hepatic Cells in Liver Diseases. Int. J. Mol. Sci. 2019, 20, 2180.
  12. Ramos, M.J.; Bandiera, L.; Menolascina, F.; Fallowfield, J.A. In vitro models for non-alcoholic fatty liver disease: Emerging platforms and their applications. iScience 2021, 25, 103549.
  13. Gambino, R.; Bugianesi, E.; Rosso, C.; Mezzabotta, L.; Pinach, S.; Alemanno, N.; Saba, F.; Cassader, M. Different Serum Free Fatty Acid Profiles in NAFLD Subjects and Healthy Controls after Oral Fat Load. Int. J. Mol. Sci. 2016, 17, 479.
  14. Cansanção, K.; Monteiro, L.S.; Leite, N.C.; Dávalos, A.; Carmo, M.G.T.; Peres, W.A.F. Advanced liver fibrosis is independently associated with palmitic acid and insulin levels in patients with non-alcoholic fatty liver disease. Nutrients 2018, 10, 1586.
  15. Hliwa, A.; Ramos-Molina, B.; Laski, D.; Mika, A.; Sledzinski, T. The Role of Fatty Acids in Non-Alcoholic Fatty Liver Disease Progression: An Update. Int. J. Mol. Sci. 2021, 22, 6900.
  16. Lujan, P.V.; Esmel, E.V.; Meseguer, E.S. Overview of Non-Alcoholic Fatty Liver Disease (NAFLD) and the Role of Sugary Food Consumption and Other Dietary Components in Its Development. Nutrients 2021, 13, 1442.
  17. Zhou, X.; Zhu, X.; Li, C.; Li, Y.; Ye, Z.; Shapiro, V.S.; Copland, J.A.; Hitosugi, T.; Bernlohr, D.A.; Sun, J.; et al. Stearoyl-CoA Desaturase-Mediated Monounsaturated Fatty Acid Availability Supports Humoral Immunity. Cell Rep. 2021, 34, 108601.
  18. Ducheix, S.; Piccinin, E.; Peres, C.; Garcia-Irigoyen, O.; Bertrand-Michel, J.; Fouache, A.; Cariello, M.; Lobaccaro, J.; Guillou, H.; Sabbà, C.; et al. Reduction in gut-derived MUFAs via intestinal stearoyl-CoA desaturase 1 deletion drives susceptibility to NAFLD and hepatocarcinoma. Hepatol. Commun. 2022, 6, 2937–2949.
  19. Geng, Y.; Faber, K.N.; de Meijer, V.E.; Blokzijl, H.; Moshage, H. How does hepatic lipid accumulation lead to lipotoxicity in non-alcoholic fatty liver disease? Hepatol. Int. 2021, 15, 21–35.
  20. Friedman, S.L.; Neuschwander-Tetri, B.A.; Rinella, M.; Sanyal, A.J. Mechanisms of NAFLD development and therapeutic strategies. Nat. Med. 2018, 24, 908–922.
  21. Tarantino, G.; Finelli, C.; Colao, A.; Capone, D.; Tarantino, M.; Grimaldi, E.; Chianese, D.; Gioia, S.; Pasanisi, F.; Contaldo, F.; et al. Are hepatic steatosis and carotid intima media thickness associated in obese patients with normal or slightly elevated gamma-glutamyl-transferase? J. Transl. Med. 2012, 10, 50.
  22. Zhao, J.; Hu, Y.; Peng, J. Targeting programmed cell death in metabolic dysfunction-associated fatty liver disease (MAFLD): A promising new therapy. Cell Mol. Biol. Lett. 2021, 26, 17.
  23. Parthasarathy, G.; Revelo, X.; Malhi, H. Pathogenesis of Nonalcoholic Steatohepatitis: An Overview. Hepatol. Commun. 2020, 4, 478–492.
  24. Tan, Z.; Sun, H.; Xue, T.; Gan, C.; Liu, H.; Xie, Y.; Yao, Y.; Ye, T. Liver Fibrosis: Therapeutic Targets and Advances in Drug Therapy. Front. Cell Dev. Biol. 2021, 9, 730176.
  25. Lee, J.; Vali, Y.; Boursier, J.; Duffin, K.; Verheij, J.; Brosnan, M.J.; Zwinderman, K.; Anstee, Q.M.; Bossuyt, P.M.; Zafarmand, M.H. Accuracy of cytokeratin 18 (M30 and M65) in detecting non-alcoholic steatohepatitis and fibrosis: A systematic review and meta-analysis. PLoS ONE 2020, 15, e0238717.
  26. Natarajan, S.K.; Bruett, T.; Muthuraj, P.G.; Sahoo, P.K.; Power, J.; Mott, J.L.; Hanson, C.; Anderson-Berry, A. Saturated free fatty acids induce placental trophoblast lipoapoptosis. PLoS ONE 2021, 16, e0249907.
  27. Hao, Q.; Chen, J.; Lu, H.; Zhou, X. The ARTS of p53-dependent mitochondrial apoptosis. J. Mol. Cell Biol. 2022, 14, mjac074.
  28. Sharma, B.; John, S. Nonalcoholic Steatohepatitis (NASH). In Treasure Island; StatPearls Publishing: Tampa, FL, USA, 2022.
  29. Mendez-Sanchez, N.; Cruz-Ramon, V.C.; Ramirez-Perez, O.L.; Hwang, J.P.; Barranco-Fragoso, B.; Cordova-Gallardo, J. New Aspects of Lipotoxicity in Nonalcoholic Steatohepatitis. Int. J. Mol. Sci. 2018, 19, 2034.
  30. Huang, X.; Yang, G.; Zhao, L.; Yuan, H.; Chen, H.; Shen, T.; Tang, W.; Man, Y.; Ma, J.; Ma, Y.; et al. Protein Phosphatase 4 Promotes Hepatocyte Lipoapoptosis by Regulating RAC1/MLK3/JNK Pathway. Oxidative Med. Cell Longev. 2021, 2021, 5550498.
  31. Saponaro, C.; Sabatini, S.; Gaggini, M.; Carli, F.; Rosso, C.; Positano, V.; Armandi, A.; Caviglia, G.P.; Faletti, R.; Bugianesi, E.; et al. Adipose tissue dysfunction and visceral fat are associated with hepatic insulin resistance and severity of NASH even in lean individuals. Liver Int. 2022, 42, 2418–2427.
  32. Patel, K.K.; Sehgal, V.S.; Kashfi, K. Molecular targets of statins and their potential side effects: Not all the glitter is gold. Eur. J. Pharmacol. 2022, 922, 174906.
  33. Zhu, B.; Liu, B.; Tang, G.; Jin, P.; Liu, D. Two cases report of febuxostat-induced acute liver injury: Acute heart failure as a probable risk factor? Drug Chem. Toxicol. 2023, 1–5, ahead of print.
  34. Wang, X.; Rao, J.; Tan, Z.; Xun, T.; Zhao, J.; Yang, X. Inflammatory signaling on cytochrome P450-mediated drug metabolism in hepatocytes. Front. Pharmacol. 2022, 13, 1043836.
  35. Nie, L.; Cai, S.-Y.; Shao, J.-Z.; Chen, J. Toll-Like Receptors, Associated Biological Roles, and Signaling Networks in Non-Mammals. Front. Immunol. 2018, 9, 1523.
  36. McKernan, K.; Varghese, M.; Patel, R.; Singer, K. Role of TLR4 in the induction of inflammatory changes in adipocytes and macrophages. Adipocyte 2020, 9, 212–222.
  37. Yu, J.; Zhu, C.; Wang, X.; Kim, K.; Bartolome, A.; Dongiovanni, P.; Yates, K.P.; Valenti, L.; Carrer, M.; Sadowski, T.; et al. Hepatocyte TLR4 triggers inter-hepatocyte Jagged1/Notch signaling to determine NASH-induced fibrosis. Sci. Transl. Med. 2021, 13, abe1692.
  38. Zhou, Y.; Feng, Y.; Yang, L.; Zheng, P.; Hang, L.; Jiang, F.; Yuan, J.; Zhu, L. High-fat diet combined with dextran sulfate sodium failed to induce a more serious NASH phenotype than high-fat diet alone. Front. Pharmacol. 2022, 13, 1022172.
  39. Carotti, S.; Guarino, M.P.; Vespasiani-Gentilucci, U.; Morini, S. Starring role of toll-like receptor-4 activation in the gut-liver axis. World J. Gastrointest. Pathophysiol. 2015, 6, 99–109.
  40. Song, Q.; Zhang, X. The Role of Gut–Liver Axis in Gut Microbiome Dysbiosis Associated NAFLD and NAFLD-HCC. Biomedicines 2022, 10, 524.
  41. Elmore, S. Apoptosis: A review of programmed cell death. Toxicol. Pathol. 2007, 35, 495–516.
  42. Thorburn, A. Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) Pathway Signaling. J. Thorac. Oncol. 2007, 2, 461–465.
  43. Tummers, B.; Green, D.R. Caspase-8: Regulating life and death. Immunol. Rev. 2017, 277, 76–89.
  44. Kanda, T.; Matsuoka, S.; Yamazaki, M.; Shibata, T.; Nirei, K.; Takahashi, H.; Kaneko, T.; Fujisawa, M.; Higuchi, T.; Nakamura, H.; et al. Apoptosis and non-alcoholic fatty liver diseases. World J. Gastroenterol. 2018, 24, 2661–2672.
  45. Pizzino, G.; Irrera, N.; Cucinotta, M.; Pallio, G.; Mannino, F.; Arcoraci, V.; Squadrito, F.; Altavilla, D.; Bitto, A. Oxidative Stress: Harms and Benefits for Human Health. Oxid. Med. Cell Longev. 2017, 2017, 8416763.
  46. Snezhkina, A.V.; Kudryavtseva, A.V.; Kardymon, O.L.; Savvateeva, M.V.; Melnikova, N.V.; Krasnov, G.S.; Dmitriev, A.A. ROS Generation and Antioxidant Defense Systems in Normal and Malignant Cells. Oxidative Med. Cell Longev. 2019, 2019, 6175804.
  47. Leyane, T.S.; Jere, S.W.; Houreld, N.N. Oxidative Stress in Ageing and Chronic Degenerative Pathologies: Molecular Mechanisms Involved in Counteracting Oxidative Stress and Chronic Inflammation. Int. J. Mol. Sci. 2022, 23, 7273.
  48. Wang, W.; Ren, J.; Zhou, W.; Huang, J.; Wu, G.; Yang, F.; Yuan, S.; Fang, J.; Liu, J.; Jin, Y.; et al. Lean non-alcoholic fatty liver disease (Lean-NAFLD) and the development of metabolic syndrome: A retrospective study. Sci. Rep. 2022, 12, 10977.
  49. Chen, Z.; Tian, R.; She, Z.; Cai, J.; Li, H. Role of oxidative stress in the pathogenesis of nonalcoholic fatty liver disease. Free Radic. Biol. Med. 2020, 152, 116–141.
  50. Kaarniranta, K.; Pawlowska, E.; Szczepanska, J.; Jablkowska, A.; Blasiak, J. Role of Mitochondrial DNA Damage in ROS-Mediated Pathogenesis of Age-Related Macular Degeneration (AMD). Int. J. Mol. Sci. 2019, 20, 2374.
  51. Li, A.; Zheng, N.; Ding, X. Mitochondrial abnormalities: A hub in metabolic syndrome-related cardiac dysfunction caused by oxidative stress. Heart Fail. Rev. 2022, 27, 1387–1394.
  52. Kim, H.-E.; Du, F.; Fang, M.; Wang, X. Formation of apoptosome is initiated by cytochrome c-induced dATP hydrolysis and subsequent nucleotide exchange on Apaf-1. Proc. Natl. Acad. Sci. USA 2005, 102, 17545–17550.
  53. Parrish, A.B.; Freel, C.D.; Kornbluth, S. Cellular Mechanisms Controlling Caspase Activation and Function. Cold Spring Harb. Perspect. Biol. 2013, 5, a008672.
  54. Di Ciaula, A.; Passarella, S.; Shanmugam, H.; Noviello, M.; Bonfrate, L.; Wang, D.Q.-H.; Portincasa, P. Nonalcoholic Fatty Liver Disease (NAFLD). Mitochondria as Players and Targets of Therapies? Int. J. Mol. Sci. 2021, 22, 5375.
  55. Ramanathan, R.; Ali, A.H.; Ibdah, J.A. Mitochondrial Dysfunction Plays Central Role in Nonalcoholic Fatty Liver Disease. Int. J. Mol. Sci. 2022, 23, 7280.
  56. Talukdar, R.; Sareen, A.; Zhu, H.; Yuan, Z.; Dixit, A.; Cheema, H.; George, J.; Barlass, U.; Sah, R.; Garg, S.K.; et al. Release of Cathepsin B in Cytosol Causes Cell Death in Acute Pancreatitis. Gastroenterology 2016, 151, 747–758.e5.
  57. Moles, A.; Tarrats, N.; Fernández-Checa, J.C.; Marí, M. Cathepsins B and D drive hepatic stellate cell proliferation and promote their fibrogenic potential. Hepatology 2009, 49, 1297–1307.
  58. Phillips, M.J.; Voeltz, G.K. Structure and function of ER membrane contact sites with other organelles. Nat. Rev. Mol. Cell Biol. 2016, 17, 69–82.
  59. Bravo, R.; Parra, V.; Gatica, D.; Rodriguez, A.E.; Torrealba, N.; Paredes, F.; Wang, Z.V.; Zorzano, A.; Hill, J.A.; Jaimovich, E.; et al. Endoplasmic Reticulum and the Unfolded Protein Response: Dynamics and Metabolic Integration. Int. Rev. Cell Mol. Biol. 2013, 301, 215–290.
  60. Cirone, M. ER Stress, UPR Activation and the Inflammatory Response to Viral Infection. Viruses 2021, 13, 798.
  61. Szegezdi, E.; Logue, S.E.; Gorman, A.M.; Samali, A. Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep. 2006, 7, 880–885.
  62. Ben-Dror, K.; Birk, R. Oleic acid ameliorates palmitic acid-induced ER stress and inflammation markers in naive and cerulein-treated exocrine pancreas cells. Biosci. Rep. 2019, 39, bsr20190054.
  63. Alkhouri, N.; Carter-Kent, C.; Feldstein, A.E. Apoptosis in nonalcoholic fatty liver disease: Diagnostic and therapeutic implications. Expert Rev. Gastroenterol. Hepatol. 2011, 5, 201–212.
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