Molecular Pathogenesis of Nonalcoholic Steatohepatitis

Alisi, Anna; Nobili, Valério; Otogawa, Kohji; Kawada, Norifumi

doi:10.2353/ajpath.2007.070463

Cited by 2 publications

(3 citation statements)

References 11 publications

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“…The available evidence suggests that, by favouring mitochondrial permeability transition, oxidative stress promotes hepatocyte necrosis and/or apoptosis. Moreover, oxidative mechanisms contribute to liver fibrosis by triggering the release of pro-fibrotic cytokines and collagen gene expression in hepatic stellate cells (19)(20)(21)(22)(23). In addition, it is relevant that protein glutathionylation, often altered during oxidative stressdependent hepatic damage, plays a pivotal role in the pathogenesis of several liver diseases, such as NAFLD (24,25).…”

Section: Introductionmentioning

confidence: 99%

Glutathionylation of p65NF-κB correlates with proliferating/apoptotic hepatoma cells exposed to pro- and anti-oxidants

Alisi

Piemonte²,

Pastore³

et al. 2009

Int J Mol Med

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Abstract.Oxidative stress influences a variety of regulatory proteins, including nuclear factor-κB (NF-κB). NF-κB is critical for maintaining the proliferation/apoptosis balance in hepatocytes. In this study we investigated the causal links between glutathione, NF-κB and hepatocyte damage. HepG2 and 3B cells were exposed to different doses of H 2 O 2 or N-acetylcysteine (NAC) and the proliferation/apoptosis rate, glutathione forms, and p65NF-κB glutathionylation and activity were analysed. Our results demonstrate that H 2 O 2 stopped proliferative response at low doses, but induced apoptosis only at high doses. In contrast, NAC exerted, proportionally to its concentration, a dual role simultaneously increasing both proliferation and apoptosis. Interestingly, the levels of proteinbound glutathione were increased by H 2 O 2 and decreased by NAC. Moreover, the antibody recognizing the glutathionylated proteins co-precipitated and -localized with the cytoplasmic inactive form of p65NF-κB in H 2 O 2 -and NAC-treated cells, even when, in 1 mM NAC-treated cells, a part of p65 was glutathione-free and localized into the nucleus. Apoptotic cells were characterised principally by a cytoskeletal staining of glutathionylation and retention of NF-κB in the cytoplasmic region; whereas in proliferating cells, glutathionylated proteins were concentrated into the perinuclear region and p65NF-κB was traslocated into the nucleus. While cytoplasmic NF-κB retention correlated well with an increased apoptotic rate, a greater expression of this protein was observed in association with the NAC-dependent. In conclusion, our findings suggest that glutathionylation inhibits NF-κB activity causing reduced hepatocyte survival, which is common in several liver diseases.

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Section: Introductionmentioning

confidence: 99%

Glutathionylation of p65NF-κB correlates with proliferating/apoptotic hepatoma cells exposed to pro- and anti-oxidants

Alisi

Piemonte²,

Pastore³

et al. 2009

Int J Mol Med

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“…NAFLD may be limited to the fatty liver alone, or it may progress to nonalcoholic steatohepatitis (NASH) (Alisi and Nobili 2007). Although the etiology of NASH is unknown, it is frequently associated with obesity, type II diabetes mellitus, and hyperlipidemia.…”

Section: Livermentioning

confidence: 99%

“…There is a great urgency to clarify the pathogenesis of NAFLD/NASH to establish reasonable treatment strategies (Alisi and Nobili 2007). Further understanding of the role of OxPL in NAFLD/NASH may lead to development of such strategies.…”

Section: Livermentioning

confidence: 99%

The Role of Phospholipid Oxidation Products in Inflammatory and Autoimmune Diseases

Leitinger

Subcellular Biochemistry

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Since the discovery of oxidized phospholipids (OxPL) and their implication as modulators of inflammation in cardiovascular disease, roles for these lipid oxidation products have been suggested in many other disease settings. Lipid oxidation products accumulate in inflamed and oxidatively damaged tissue, where they are derived from oxidative modification of lipoproteins, but also from membranes of cells undergoing apoptosis. Thus, increased oxidative stress as well as decreased clearance of apoptotic cells has been implied to contribute to accumulation of OxPL in chronically inflamed tissues.A central role for OxPL in disease states associated with dyslipedemia, including atherosclerosis, diabetes and its complications, metabolic syndrome, and renal insufficiency, as well as general prothrombotic states, has been proposed. In addition, in organs which are constantly exposed to oxidative stress, including lung, skin, and eyes, increased levels of OxPL are suggested to contribute to inflammatory conditions. Moreover, accumulation of OxPL causes general immunmodulation and may lead to autoimmune diseases. Evidence is accumulating that OxPL play a role in lupus erythematosus, antiphospholipid syndrome, and rheumatoid arthritis. Last but not least, a role for OxPL in neurological disorders including multiple sclerosis (MS), Alzheimer's and Parkinson's disease has been suggested.This chapter will summarize recent findings obtained in animal models and from studies in humans that indicate that formation of OxPL represents a general mechanism that may play a major role in chronic inflammatory and autoimmune diseases.

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Molecular Pathogenesis of Nonalcoholic Steatohepatitis

Cited by 2 publications

References 11 publications

Glutathionylation of p65NF-κB correlates with proliferating/apoptotic hepatoma cells exposed to pro- and anti-oxidants

Glutathionylation of p65NF-κB correlates with proliferating/apoptotic hepatoma cells exposed to pro- and anti-oxidants

The Role of Phospholipid Oxidation Products in Inflammatory and Autoimmune Diseases

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