A Silybin-Phospholipid Complex Prevents Mitochondrial Dysfunction in a Rodent Model of Nonalcoholic Steatohepatitis

Serviddio, Gaetano; Bellanti, Francesco; Giudetti, Anna Maria; Gnoni, Gabriele V.; Petrella, A.; Tamborra, Rosanna; Romano, Antonino Davide; Rollo, Tiziana; Vendemiale, Gianluigi; Altomare, Emanuele

doi:10.1124/jpet.109.161612

Cited by 60 publications

(29 citation statements)

References 49 publications

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“…Mitochondria are a target of oxidative stress, but also the main source of free radicals and the impairment in MRC activity is directly responsible for the increase in cellular ROS in a vicious cycle [13]. Our results are consistent with previous findings on MRC restoration by silibinin in a rodent model of iron overload [20] and with recent data in another model of NASH [39].…”

Section: Discussionsupporting

confidence: 92%

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: Discussionsupporting

confidence: 92%

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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“…Although in the rodent models of NAFLD/NASH the development of fibrosis is modest [30,36], in our hands, the administration of CGS21680 to rats fed on an MCD diet does not worsen fibrosis markers. On the contrary, CGS21680 significantly reduces the number of α-SMA-positive activated HSCs and the expression of TGFβ and type I procollagen α mRNAs in NASH livers.…”

Section: Figure 5 Cgs21680 Treatment Prevents Hepatocyte Apoptosis Anmentioning

confidence: 70%

Adenosine A2a receptor stimulation prevents hepatocyte lipotoxicity and non-alcoholic steatohepatitis (NASH) in rats

Imarisio¹,

Alchera²,

Sutti³

et al. 2012

Clinical Science

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NEFA (non-esterified 'free' fatty acid)-mediated lipotoxicity plays a critical role in the pathogenesis of NASH (non-alcoholic steatohepatitis). In the light of the growing need for new therapeutic options for NASH, we investigated the action of A2aR (adenosine A(2a) receptor) stimulation against lipotoxicity. The effects of the A(2a)R agonist CGS21680 [2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxyamidoadenosine] were evaluated 'in vitro' in liver cells exposed to SA (stearic acid) and 'in vivo' in rats with NASH induced by 8 weeks of feeding with an MCD diet (methionine/choline-deficient diet). In cultured hepatocytes, SA promoted apoptosis by inducing MKK4 (mitogen-activated protein kinase kinase 4)/SEK1 (stress-activated protein kinase/extracellular-signal-regulated kinase kinase-1) and JNK-1/2 (c-Jun N-terminal kinase-1/2) activation. CGS21680 addition prevented JNK-1/2 activation and reduced apoptosis without interfering with lipid accumulation. CGS21680 action required PI3K (phosphoinositide 3-kinase)/Akt-mediated block of MKK4/SEK1. Consistently, PI3K inhibition with wortmannin abolished the cytoprotective action of CGS21680 and reverted MKK4 inhibition. SA lipotoxicity was also prevented by transfecting HTC cells with a specific MKK4/SEK1 siRNA (small interfering RNA). In rats receiving the MCD diet, the development of NASH was associated with MKK4/SEK1 and JNK-1/2 activation. CGS21680 (0.5 mg/kg of body weight, intraperitoneal) administration to MCD-fed rats prevented JNK-1/2 activation by acting on MKK4/SEK1. CGS21680 also effectively reduced NASH-associated ALT (alanine aminotransferase) release, hepatocyte apoptosis, liver inflammation and fibrosis without affecting hepatic steatosis. Taken together, these results demonstrate that, by inhibiting JNK-1/2, A(2a)R stimulation reduces lipotoxicity and ameliorates NASH, giving a rationale to investigate A(2a)R agonists as possible new therapeutic agents in preventing fatty liver progression to NASH.

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“…36 The effect of silibinin on nitrosative stress may explain the efficacy of this compound in preserving mitochondrial respiration, which has been demonstrated in a rodent model of iron overload 37 and in another model of NASH. 38 The cellular redox status is also one of the main stimuli for NFkB activation. 39 NFkB is the master transcription factor in the control of molecular pathways related to inflammation.…”

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

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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;

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A Silybin-Phospholipid Complex Prevents Mitochondrial Dysfunction in a Rodent Model of Nonalcoholic Steatohepatitis

Cited by 60 publications

References 49 publications

Silibinin improves hepatic and myocardial injury in mice with nonalcoholic steatohepatitis

Silibinin improves hepatic and myocardial injury in mice with nonalcoholic steatohepatitis

Adenosine A2a receptor stimulation prevents hepatocyte lipotoxicity and non-alcoholic steatohepatitis (NASH) in rats

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

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