Uncoupling protein-2 (UCP2) induces mitochondrial proton leak and increases susceptibility of non-alcoholic steatohepatitis (NASH) liver to ischaemia-reperfusion injury

Serviddio, Gaetano; Bellanti, Francesco; Tamborra, Rosanna; Rollo, Tiziana; Capitanio, Nazzareno; Romano, Antonino Davide; Sastre, Juan; Vendemiale, Gianluigi; Altomare, Emanuele

doi:10.1136/gut.2007.147496

Cited by 194 publications

(198 citation statements)

References 47 publications

Supporting

Mentioning

187

Contrasting

Unclassified

Order By: Relevance

“…The initiation and perpetuation of cell injury in NAFLD is associated with the increase of free radicals and the depletion of endogenous anti-oxidant defense both in human and rodents [26,27]. Several data suggest that lipotoxicity plays a crucial role also in the pathogenesis of cardiomyopathy underlying nonischemic chronic heart failure, a leading cause of death in patients with obesity and/or diabetes [9,16].…”

Section: Discussionmentioning

confidence: 99%

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

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

show abstract

“…Consistent with this outcome, previous studies reported the depletion of this pool of GSH during hepatic I/R damage, and its restoration by GSH ethyl ester [37] or SAM [38] protected steatotic livers against I/R damage. Although this concept remains to be tested in human fatty liver, mitochondrial GSH depletion has been shown in nonalcoholic steatohepatitis [39] which is associated with increased free cholesterol accumulation and StAR overexpression [40]. If confirmed the role of …”

Section: Jhepat-d-10-00907-r Llacuna Et Al 18mentioning

confidence: 98%

Targeting cholesterol at different levels in the mevalonate pathway protects fatty liver against ischemia–reperfusion injury

Llacuna

Fernández

Montfort

et al. 2011

Journal of Hepatology

View full text Add to dashboard Cite

show abstract

“…29 Oxidative stress is mirrored by the increase of lipid peroxidation products (ie, malondialdehyde and hydroxynonenal) in patients with NASH and in animal models. [30][31][32] The importance of oxidative stress in the pathogenesis of steatohepatitis is underscored by the use of several antioxidants, associated with variable success, in patients with NASH; 33 a recent randomized controlled trial showed the efficacy of vitamin E in counteracting liver injury progression. 34 There is evidence that both ROS and RNS contribute to hepatocyte damage and inflammatory/fibrogenic cells activation.…”

Section: Discussionmentioning

confidence: 99%

Silibinin modulates lipid homeostasis and inhibits nuclear factor kappa B activation in experimental nonalcoholic steatohepatitis

Salamone

Galvano

Cappello

et al. 2012

Translational Research

110

View full text Add to dashboard Cite

Nonalcoholic steatohepatitis (NASH) is associated with increased liver-related mortality. Disturbances in hepatic lipid homeostasis trigger oxidative stress and inflammation (ie, lipotoxicity), leading to the progression of NASH. This study aimed at identifying whether silibinin may influence the molecular events of lipotoxicity in a mouse model of NASH. Eight-week-old db/db mice were fed a methioninecholine deficient (MCD) diet for 4 weeks and treated daily with silibinin (20 mg/kg intraperitoneally) or vehicle. Liver expression and enzyme activity of stearoyl-CoA desaturase-1 and acyl-CoA oxidase, and expression of liver fatty acid-binding protein were assessed. Hepatic levels of reactive oxygen species, thiobarbituric acidreactive substances (TBARS), 3-nitrotyrosine (3-NT), inducible nitric oxide synthase (iNOS), and nuclear factor kappa B (NFkB) activities were also determined. Silibinin administration decreased serum alanine aminotransferase and improved liver steatosis, hepatocyte ballooning, and lobular inflammation in db/db mice fed an MCD diet. Gene expression and activity of stearoyl-CoA desaturase-1 were reduced in db/db mice fed an MCD diet compared with lean controls and were increased by silibinin; moreover, silibinin treatment induced the expression and activity of acylCoA oxidase and the expression of liver fatty acid-binding protein. Vehicle-treated animals displayed increased hepatic levels of reactive oxygen species and TBARS, 3-NT staining, and iNOS expression; silibinin treatment markedly decreased reactive oxygen species and TBARS and restored 3-NT and iNOS to the levels of control mice. db/db mice fed an MCD diet consistently had increased NFkB p65 and p50 binding activity; silibinin administration significantly decreased the activity of both subunits. Silibinin treatment counteracts the progression of liver injury by modulating lipid homeostasis and suppressing oxidative stress-mediated lipotoxicity and NFkB activation in experimental NASH. (Translational Research 2012;159:477-486) Abbreviations: AOX ¼ acyl-CoA oxidase; ALT ¼ alanine aminotransferase; FFA ¼ free fatty acid; iNOS ¼ inducible nitric oxide synthase; L-FABP ¼ liver-fatty acid binding protein;

show abstract

Uncoupling protein-2 (UCP2) induces mitochondrial proton leak and increases susceptibility of non-alcoholic steatohepatitis (NASH) liver to ischaemia-reperfusion injury

Cited by 194 publications

References 47 publications

Silibinin improves hepatic and myocardial injury in mice with nonalcoholic steatohepatitis

Silibinin improves hepatic and myocardial injury in mice with nonalcoholic steatohepatitis

Targeting cholesterol at different levels in the mevalonate pathway protects fatty liver against ischemia–reperfusion injury

Silibinin modulates lipid homeostasis and inhibits nuclear factor kappa B activation in experimental nonalcoholic steatohepatitis

Contact Info

Product

Resources

About