Uric acid and anti-TNF antibody improve mitochondrial dysfunction in ob/ob mice

García-Ruiz, Inmaculada; Rodríguez‐Juan, Cristina; Díaz-Sanjuán, Teresa; Hoyo, Pilar del; Colina, Francisco; Muņoz‐Yagüe, Teresa; Solı́s-Herruzo, José A.

doi:10.1002/hep.21313

Cited by 166 publications

(176 citation statements)

References 48 publications

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“…Noteworthy, TNF-␣ and oxidative stress plays a sinergic role for the progression of heart failure [41] and the vicious cycle inflammation-oxidative stress represents a main target for preventing myocardial damage [41]. Consistently with the observed improvement of mitochondrial function [42], silibinin administration decreased also TNF-␣ gene expression in the liver. Surprisingly, IL-6 expression was decreased in the liver and in the myocardium of db/db mice fed MCD diet.…”

Section: Discussionmentioning

confidence: 68%

Silibinin improves hepatic and myocardial injury in mice with nonalcoholic steatohepatitis

Salamone¹,

Galvano²,

Marino³

et al. 2012

Digestive and Liver Disease

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a b s t r a c tBackground: Nonalcoholic fatty liver disease is a chronic metabolic disorder with significant impact on cardiovascular and liver mortality. Aims: In this study, we examined the effects of silibinin on liver and myocardium injury in an experimental model of nonalcoholic fatty liver disease. Methods: A four-week daily dose of silibinin (20 mg/kg i.p.) was administrated to db/db mice fed a methionine-choline deficient diet. Hepatic and myocardial histology, oxidative stress and inflammatory cytokines were evaluated. Results: Silibinin administration decreased HOMA-IR, serum ALT and markedly improved hepatic and myocardial damage. Silibinin reduced isoprostanes, 8-deoxyguanosine and nitrites/nitrates in the liver and in the heart of db/db fed the methionine-choline deficient diet, whereas glutathione levels were restored to lean mice levels in both tissues. Consistently, liver mitochondrial respiratory chain activity was significantly impaired in untreated mice and was completely restored in silibinin-treated animals. TNF-␣ was increased whereas IL-6 was decreased both in the liver and heart of db/db fed methionine-choline deficient diet. Silibinin reversed heart TNF-␣ and IL-6 expression to control mice levels. Indeed, liver JNK phosphorylation was reduced to control levels in treated animals. Conclusions: This study demonstrates a combined effectiveness of silibinin on improving liver and myocardial injury in experimental nonalcoholic fatty liver disease.

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Section: Discussionmentioning

confidence: 68%

Silibinin improves hepatic and myocardial injury in mice with nonalcoholic steatohepatitis

Salamone¹,

Galvano²,

Marino³

et al. 2012

Digestive and Liver Disease

View full text Add to dashboard Cite

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“…Studies also report increased iNOS expression in liver of ob/ob mice [53], CCl 4 -induced steatotic liver following normothermic ischemia [95], and in the obese fa/fa rat exposed to binge alcohol [5]. This is important for hepatotoxicity because NO and peroxynitrite (ONOO − ) are known to mediate mitochondrial dysfunction [96,97] and increases in iNOS expression in fatty liver are correlated with nitration of mitochondrial proteins [53,98]. Moreover, NO regulates mitochondrial respiration through reversible binding at the redoxactive heme site in cytochrome c oxidase [99][100][101] and affects mitochondrial biogenesis through interactions with soluble guanylate cyclase [102].…”

Section: Interplay Between Nitric Oxide and Mitochondria In Fatty LIVmentioning

confidence: 96%

“…Decreased activity of all five oxidative phosphorylation complexes was found in liver biopsies from human patients with NASH as compared to normal liver [52]. Similarly, decreased respiratory complex activities were also measured in the livers of ob/ob mice [53]. While these studies clearly point to a defect in mitochondrial bioenergetics, additional studies are required to identify and better understand the molecular mechanisms and targets responsible for mitochondrial dysfunction in obesity induced fatty liver disease.…”

Section: Mitochondria Dysfunction In Fatty Liver Diseases -Bioenergetmentioning

confidence: 97%

“…Conflicting effects of obesity and NAFLD on mitochondrial GSH levels have also been reported. For example, decreased [53] and increased [61] levels of mitochondrial GSH have been reported in liver of ob/ob mice. In addition, two glutathione-replenishing agents, S-adenosylmethionine and 2(RS)-npropylthiazolidine-4(R)-carboxylic acid (i.e.…”

Section: Mitochondria Dysfunction In Fatty Liver Diseases -Bioenergetmentioning

confidence: 99%

“…In normal healthy liver iNOS levels are very low or undetectable [91], whereas during inflammation and other disease states iNOS levels are increased in liver due to infiltrating inflammatory cells and via induction in Kupffer cells (resident liver macrophage), hepatocytes, and biliary epithelial cells [92][93][94]. Studies also report increased iNOS expression in liver of ob/ob mice [53], CCl 4 -induced steatotic liver following normothermic ischemia [95], and in the obese fa/fa rat exposed to binge alcohol [5]. This is important for hepatotoxicity because NO and peroxynitrite (ONOO − ) are known to mediate mitochondrial dysfunction [96,97] and increases in iNOS expression in fatty liver are correlated with nitration of mitochondrial proteins [53,98].…”

Section: Interplay Between Nitric Oxide and Mitochondria In Fatty LIVmentioning

confidence: 99%

See 2 more Smart Citations

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

Mantena

King

Andringa

et al. 2008

Free Radical Biology and Medicine

381

302

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Fatty liver disease associated with chronic alcohol consumption or obesity/type 2 diabetes has emerged as a serious public health problem. Steatosis, accumulation of triglyceride in hepatocytes, is now recognized as a critical "first-hit" in the pathogenesis of liver disease. It is proposed that steatosis "primes" the liver to progress to more severe liver pathologies when individuals are exposed to subsequent metabolic and/or environmental stressors or "second-hits". Genetic risk factors can also influence the susceptibility and severity of fatty liver disease. Furthermore, oxidative stress, disrupted nitric oxide (NO) signaling, and mitochondrial dysfunctional are proposed to be key molecular events that accelerate or worsen steatosis and initiate progression to steatohepatitis and fibrosis. This review article will discuss the following topics regarding the pathobiology and molecular mechanisms responsible for fatty liver disease: 1) the "two-hit" or "multi-hit" hypothesis; 2) the role of mitochondrial bioenergetic defects and oxidant stress; 3) interplay between NO and mitochondria in fatty liver disease; 4) genetic risk factors and oxidative stress responsive genes; and 5) the feasibility of antioxidants for treatment.

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Assessment of Mitochondrial Dysfunction by Microscopy

Pruimboom‐Brees

Boucher

Jakowski

et al. 2008

Drug‐Induced Mitochondrial Dysfunction

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Uric acid and anti-TNF antibody improve mitochondrial dysfunction in ob/ob mice

Abstract: The mechanisms responsible for low mitochondrial respiratory chain (MRC) activity in the liver of patients with nonalcoholic steatohepatitis are unknown. In this study, we examined the cause of this dysfunction in ob/ob mice.

Cited by 166 publications

References 48 publications

Silibinin improves hepatic and myocardial injury in mice with nonalcoholic steatohepatitis

Silibinin improves hepatic and myocardial injury in mice with nonalcoholic steatohepatitis

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

Assessment of Mitochondrial Dysfunction by Microscopy

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