Multiple Hits, Including Oxidative Stress, as Pathogenesis and Treatment Target in Non-Alcoholic Steatohepatitis (NASH)

Takaki, Akinobu; Kawai, Daisuke; Yamamoto, Kazuhide

doi:10.3390/ijms141020704

Cited by 353 publications

(322 citation statements)

References 138 publications

(138 reference statements)

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“…42 Several concepts involving dual hits and multiple-hit paradigms have been proposed but have been the focus of debate. 43,44 The lipotoxicity-based model that includes the generation of oxidative stress after the administration of hepatotoxins, a Scores were calculated after analysis of the histological features of nonalcoholic steatohepatitis (NASH) as described by Kleiner et al 26 and in the guideline of the NIH NASH Clinical Research Network.…”

Section: Discussionmentioning

confidence: 99%

“…ajp.amjpathol.org -The American Journal of Pathology second hit, has been previously described by us and others, recognizing the fact that it does not reflect the true developmental stages of human NASH but represents an underlying condition of steatosis and insulin and leptin resistance that is found in NASH patients. 24,44 Because oxidative stress is undoubtedly a major player in human NASH, our model exemplifies a logical approach to studying oxidative stress mechanisms in the progression of NASH and can be used for testing compounds that attenuate oxidative stressemediated inflammation in this disease.…”

Section: Discussionmentioning

confidence: 99%

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NADPH Oxidase–Derived Peroxynitrite Drives Inflammation in Mice and Human Nonalcoholic Steatohepatitis via TLR4-Lipid Raft Recruitment

Das

Alhasson

Dattaroy

et al. 2015

The American Journal of Pathology

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The molecular events that link NADPH oxidase activation and the induction of Toll-like receptor (TLR)-4 recruitment into hepatic lipid rafts in nonalcoholic steatohepatitis (NASH) are unclear. We hypothesized that in liver, NADPH oxidase activation is key in TLR4 recruitment into lipid rafts, which in turn upregulates NF-kB translocation to the nucleus and subsequent DNA binding, leading to NASH progression. Results from confocal microscopy showed that liver from murine and human NASH had NADPH oxidase activation, which led to the formation of highly reactive peroxynitrite, as shown by 3-nitrotyrosine formation in diseased liver. Expression and recruitment of TLR4 into the lipid rafts were significantly greater in rodent and human NASH. The described phenomenon was NADPH oxidase, p47phox, and peroxynitrite dependent, as liver from p47phox-deficient mice and from mice treated with a peroxynitrite decomposition catalyst [iron(III) tetrakis(p-sulfonatophenyl)porphyrin] or a peroxynitrite scavenger (phenylboronic acid) had markedly less Tlr4 recruitment into lipid rafts. Mechanistically, peroxynitrite-induced TLR4 recruitment was linked to increased IL-1b, sinusoidal injury, and Kupffer cell activation while blocking peroxynitrite-attenuated NASH symptoms. The results strongly suggest that NADPH oxidaseemediated peroxynitrite drove TLR4 recruitment into hepatic lipid rafts and inflammation, whereas the in vivo use of the peroxynitrite scavenger phenylboronic acid, a novel synthetic molecule having high reactivity with peroxynitrite, attenuates inflammatory pathogenesis in NASH. (Am J Pathol 2015 http://dx

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

NADPH Oxidase–Derived Peroxynitrite Drives Inflammation in Mice and Human Nonalcoholic Steatohepatitis via TLR4-Lipid Raft Recruitment

Das

Alhasson

Dattaroy

et al. 2015

The American Journal of Pathology

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“…In fact, pentoxiphylline suppresses TNF-α gene transcription and acts as a hydroxyl and peroxyl radical scavenger [127] . Moreover, it has been proven that it increases red blood cell flexibility, reduces blood viscosity and decreases platelet aggregation.…”

Section: Other Anti-oxidant Drugsmentioning

confidence: 99%

Oxidative stress: New insights on the association of non-alcoholic fatty liver disease and atherosclerosis

Polimeni

Ben

Baratta

et al. 2015

WJH

165

136

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Non-alcoholic fatty liver disease (NAFLD) represents the most common and emerging chronic liver disease worldwide. It includes a wide spectrum of liver diseases ranging from simple fatty liver to non-alcoholic steatohepatitis (NASH), which may progress to fibrosis and more severe liver complications such as cirrhosis, hepatocellular carcinoma and liver mortality. NAFLD is strongly associated with obesity, insulin resistance, hypertension, and dyslipidaemia, and is now regarded as the liver manifestation of the metabolic syndrome. The increased mortality of patients with NAFLD is primarily a result of cardiovascular disease and, to a lesser extent, to liver related diseases. Increased oxidative stress has been reported in both patients with NAFLD and patient with cardiovascular risk factors. Thus, oxidative stress represents a shared pathophysiological disorder between the two conditions. Several therapeutic strategies targeting oxidative stress reduction in patients with NAFLD have been proposed, with conflicting results. In particular, vitamin E supplementation has been suggested for the treatment of non-diabetic, non-cirrhotic adults with active NASH, although this recommendation is based only on the results of a single randomized controlled trial. Other antioxidant treatments suggested are resveratrol, silybin, L-carnitine and pentoxiphylline. No trial so far, has evaluated the cardiovascular effects of antioxidant treatment in patients with NAFLD. New, large-scale studies including as end-point also the assessment of the atherosclerosis markers are needed.

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“…Hepatic NPCs contribute to production and secretion of multiple cytokines and inflammation-related substances, and are constantly exposed to oxidative stress [10,11].…”

Section: Ergo Is Minimally Taken Up Into Liver Parenchymal Cells Butmentioning

confidence: 99%

Localization of Xenobiotic Transporter OCTN1/SLC22A4 in Hepatic Stellate Cells and Its Protective Role in Liver Fibrosis

Tang

Masuo

Sakai

et al. 2016

Journal of Pharmaceutical Sciences

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3Xenobiotic transporters play key roles in disposition of a certain therapeutic agents although limited information is available on their roles other than pharmacokinetic issues. Here, suppressive effect of multispecific organic cation transporter OCTN1/SLC22A4 on liver fibrosis was proposed in liver injury models. After injection of hepatotoxins such as dimethylnitrosamine (DMN) or concanavalin A, hepatic fibrosis and oxidative stress, evaluated in terms of Sirius red and 4-hydroxy-2-nonenal staining, respectively, were more severe in liver of octn1/slc22a4 gene knockout (octn1 -/-) mice than that in wild-type mice. DMN treatment markedly increased α-smooth muscle actin

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Multiple Hits, Including Oxidative Stress, as Pathogenesis and Treatment Target in Non-Alcoholic Steatohepatitis (NASH)

Cited by 353 publications

References 138 publications

NADPH Oxidase–Derived Peroxynitrite Drives Inflammation in Mice and Human Nonalcoholic Steatohepatitis via TLR4-Lipid Raft Recruitment

NADPH Oxidase–Derived Peroxynitrite Drives Inflammation in Mice and Human Nonalcoholic Steatohepatitis via TLR4-Lipid Raft Recruitment

Oxidative stress: New insights on the association of non-alcoholic fatty liver disease and atherosclerosis

Localization of Xenobiotic Transporter OCTN1/SLC22A4 in Hepatic Stellate Cells and Its Protective Role in Liver Fibrosis

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