Tumor necrosis factor-α accelerates apoptosis of steatotic hepatocytes from a murine model of non-alcoholic fatty liver disease

Zhang, Wei; Kudo, Hiroshi; Kawai, Kengo; Fujisaka, Shiho; Usui, Isao; Sugiyama, Toshiro; Tsukada, Kazuhiro; Chen, Nai‐Hong; Takahara, Taro

doi:10.1016/j.bbrc.2009.12.144

Cited by 50 publications

(34 citation statements)

References 23 publications

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“…As mentioned earlier, cytosolic ONS occurs in NAFLD as a direct effect of extramitochondrial FA oxidation (1) (section ''Extramitochondrial FA oxidation'') and as an indirect effect of mitochondrial GSH depletion (187), which facilitates efflux of ROS/RNS into the cytosol (77). Thus, the viability of healthy hepatocytes is not affected by TNF-a because of adequate activation and unimpaired NF-jB signaling (180), whereas oxidatively/nitrosatively stressed steatotic hepatocytes that are stimulated with TNF-a have a predilection for apoptosis (233) because of NF-jB inhibition (Fig. 8).…”

Section: Mitochondriamentioning

confidence: 99%

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

Reiniers

Golen

Gulik

et al. 2014

Antioxidants & Redox Signaling

104

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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.

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Section: Mitochondriamentioning

confidence: 99%

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

Reiniers

Golen

Gulik

et al. 2014

Antioxidants & Redox Signaling

104

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“…This indicates that apoptosis activation by FATP4 was specific for Pal, but not for methionine/choline deficiency. We also tested whether FATP4 susceptibility during TNF-α-induced apoptosis [30]. TNF-α/cycloheximide (CHX) increased apoptosis in both cell lines (Fig.…”

Section: Fatp4 Overexpression Sensitizes Palmitate-induced Apoptosis mentioning

confidence: 99%

Palmitate activation by fatty acid transport protein 4 as a model system for hepatocellular apoptosis and steatosis

Seeßle¹,

Liebisch

Schmitz

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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“…However, impaired lipid metabolism leads to hepatocyte apoptosis in the presence of TNF α . Hepatocytes laden with lipids have increased susceptibility to TNF α -induced cell death [82, 83]. Free cholesterol accumulation in hepatocytes depletes mitochondrial glutathione.…”

Section: Inflammatory Cytokines and Nafldmentioning

confidence: 99%

“…This induces ROS generation in hepatocytes and then evokes cell death signaling [82]. In addition, lipid-accumulated hepatocytes increase the expression of ASK-1 and JNK in response to TNF α [83], which lead to cell death. These findings demonstrate that TNF α plays an important role in lipid metabolism as well as hepatocyte cell death in the development of NAFLD.…”

Section: Inflammatory Cytokines and Nafldmentioning

confidence: 99%

Role of Toll-Like Receptors and Their Downstream Molecules in the Development of Nonalcoholic Fatty Liver Disease

Miura

Seki

Ohnishi

et al. 2010

Gastroenterology Research and Practice

130

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Activation of innate immunity is associated with the development of liver disease, including non-alcoholic fatty liver disease (NAFLD). In the innate immune system, Toll-like receptors (TLRs) are sensors that recognize bacterial and viral components such as lipopolysaccharide, bacterial DNA, and peptidoglycan. Recent data have demonstrated that the liver is exposed to a high load of TLR ligands due to bacterial overgrowth and increased intestinal permeability in NAFLD. Upon stimulation by these TLR ligands, hepatic immune cells produce various mediators that are involved in host defense. On the other hand, these mediators alter lipid metabolism, insulin signaling, and cell survival. Indeed, some TLR-deficient mice demonstrate lesser degrees of NAFLD even though TLR ligands are increased. This paper will highlight the recent progress on the study of TLR signaling and their downstream molecules in the development of NAFLD.

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Tumor necrosis factor-α accelerates apoptosis of steatotic hepatocytes from a murine model of non-alcoholic fatty liver disease

Cited by 50 publications

References 23 publications

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

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

Palmitate activation by fatty acid transport protein 4 as a model system for hepatocellular apoptosis and steatosis

Role of Toll-Like Receptors and Their Downstream Molecules in the Development of Nonalcoholic Fatty Liver Disease

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