20 - World Journal of Gastroenterology

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Grattagliano I et al . Silybin and liver steatosisTable 2 Concentrations of total glutathione, thioredoxin,nitrosothiols, and activity of glutathione peroxidase,malondialdehyde-thiobarbituric acid reactive substances,nitrosothiols, nitrotyrosine, and keratin-18 in the liver of ratsDay 7 Day 14 Day 30Glutathione S 34.3 ± 3.1 33.2 ± 1.4 25.3 ± 1.2 a34.0 ± 1.3 nmol/mg prt R 35.1 ± 1.2 33.7 ± 1.0 30.9 ± 1.1 a,cThioredoxin S 14.2 ± 1.0 a 16.3 ± 2.4 a 5.2 ± 0.75.6 ± 0.9 nmol/mg prt R 11.3 ± 1.0 a 14.4 ± 1.0 a 6.2 ± 0.7 cNitrosothiols S 32.9 ± 3.5 a 30.0 ± 2.2 a 13.0 ± 1.2 a16.8 ± 4.7 pmol/mg prt R 35.4 ± 2.7 a 27.3 ± 2.2 a,c 15.8 ± 1.5 a,cMDA-TBA S 17 ± 4 a 39 ± 8 a 92 ± 10 a12 ± 3 nmol/L R 12 ± 3 19 ± 4 a,c 41 ± 9 a,cNitrosothiols S 73 ± 15 79 ± 12 a 88 ± 10 a62 ± 10 nmol/L R 67 ± 10 69 ± 10 74 ± 11 a,cNitrotyrosine S 6 ± 2 10 ± 3 a 14 ± 3 a6 ± 1 nmol/L R 5 ± 1 5 ± 2 c 10 ± 2 a,cK-18 S 222 ± 21 233 ± 16 a 289 ± 20 a198 ± 20 U/L R 210 ± 10 213 ± 13 c 240 ± 17 a,cGPx activity S 9.3 ± 1.2 a 21.1 ± 3.7 a 13.7 ± 1.8 a4.5 ± 0.4 nmol NADH/min/mg prtR 6.3 ± 0.9 a,b 20.8 ± 1.4 a 16.6 ± 2.6 a,bThe liver of rats fed a choline-deficient (CD) diet without (S)/with (R)Realsil or a normal choline-supplemented diet (controls). Values fromcontrols are reported in the first column under the parameter. Data aremean ± SD of n = 5 rats per group at each time point. a P < 0.05 vs controlrats; c P < 0.05 vs rats on CD diet without Realsil at the same time point.GPx: Glutathione peroxidase; MDA-TBA: Malondialdehyde-thiobarbituricacid reactive substances; K-18: Keratin-18; prt: Protein.intracellular metabolic processes and systemic changesoccurring in patients with fatty liver are still under debate.Also, the effect of modulating compounds andantioxidant molecules on such lipid effectors and on NOmetabolic changes has been poorly investigated. Mitochondria,coordinators of energy metabolism, are activelyinvolved in such processes [18,21] . In NASH patients, mitochondriashow morphological alterations and functionalimpairment [7,24] . Ultrastructural modifications were alsoobserved in rats fed a steatogenic diet (HFD) [25] . Mitochondriaare the most relevant source of ROS in mostcells and especially in fatty hepatocytes [26,27] . ROS alter theactivity of JNK enzymes, disturb insulin signaling, andenhance potassium transport across the inner mitochondrialmembrane [28] leading to mitochondrial uncouplingand triggering as well adaptive response [29-31] .In a recent study [3] , we observed that hepatocytes reactto fat deposition by a very early increase of GSH andthioredoxin both in the cytosol and in the mitochondriato likely prevent lipid and protein oxidation. Prolongationof steatogenic diet, however, led to major mitochondrialredox changes, i.e., increased MDA-TBA, progressivedecrease of GSH and thioredoxin, and increase of mixeddisulfides, nitrates, and nitrosothiols, all consistent withboth oxidative damage and increased NO synthesis. Infatty livers, NO synthase (iNOS) is induced by enhancedinflow of gut-derived toxins [32] and tumor necrosisfactor-α expression [33] and generates hyper reactive speciessuch as NO with accumulation of nitrotyrosine [33] .This likely reflects an increased peroxynitrite formationAMDA-TBA, nmol/g liverBMDA-TBA, nmol/g liver8060402003020100and suggests potential NO participation to liver injury [34] .Thioredoxin, a redox-active protein induced by oxidativestress [35] , is actively involved in NO regulation throughnitrosothiols cleavage [36,37] . Nitrosothiols, formed by conjugationof NO with free thiols, oppose peroxynitriteformation and act as intracellular messenger controllingcellular and mitochondrial functions [38,39] .In the fatty liver, intracellular redox changes and proteinnitrosation may represent a major factor stimulatingthe progression from simple steatosis to NASH [40] . Also,a critical role for such hepatic variations in the pathogenesisof systemic chronic inflammatory conditions hasbeen recently proposed [41,42] . In our study, we show thatliver steatosis is associated with high levels of circulatingNO derivatives (nitrosothiols and nitrotyrosine) andwith high levels of K-18, the major keratin expressed inthe liver and one of the most prominent substrates ofcaspases during hepatocytes apoptotic death [43] . Thesealterations were closely dependent on the changes occurringin the liver in which GSH content and thioredoxinactivity declined with ongoing steatosis. Also, the closea^0 7 14 28t /d0 14 30 60t /dFigure 2 Concentrations of malondialdehyde-thiobarbituric acid reactivesubstances. A: Liver of rat fed a choline-deficient diet; B: Liver of rat fed a highfat diet. Closed square: Without; open square: With Realsil administration; opencircle: Control rats fed a standard chow-diet with adequate content of choline.Data are mean ± SD of n = 5 rats per group at each time point. a P < 0.05 vscontrol rats; c P < 0.05 vs untreated rats at the same time points. MDA-TBA:Malondialdehyde-thiobarbituric.aa, caa, cWJG|www.wjgnet.com3012 May 28, 2013|Volume 19|Issue 20|
Grattagliano I et al . Silybin and liver steatosisA90aB300270aMDA-TBA, nmol/L6030aa, cK-18, U/L24021018001500 14 30 60t /d0 14 30 60t /dC100D15aaa12Nitrosothiols, nmol/L8060Nitrotyrosine, nmol/L963a, c4000 14 30 60t /d0 14 30 60t /dFigure 3 Plasma concentration of redox active and nitrogen regulating molecules. A: Malondialdehyde-thiobarbituric acid reactive substances (MDA-TBA); B:Keratine 18 (K-18); C: Nitrosothiols; D: Nitrotyrosine. Rats were fed a high fat diet without (closed square) or with (open square) Realsil administration; control rats feda standard chow-diet (open circle). Data are mean ± SD of n = 5 rats per group at each time point. a P < 0.05 vs control rats; c P < 0.05 vs untreated rats at the sametime points.Table 3 Concentrations of total glutathione, thioredoxin,nitrosothiols, and activity of glutathione peroxidase in theliver of ratDay 14 Day 30 Day 60Glutathione S 23.7 ± 1.9 a 20.8 ± 2 a 22.4 ± 2.4 a33.4 ± 0.8 nmol/mg prt R 22.3 ± 1.8 a 23.9 ± 1.7 a 23 ± 1.6 aThioredoxin S 9.2 ± 0.9 a 8.9 ± 0.8 a 4.3 ± 1.05.4 ± 0.5 nmol/mg prt R 7.6 ± 0.7 a,c 7.8 ± 0.7 a 7.4 ± 1.7 a,cNitrosothiols S 18.1 ± 1.5 19.6 ± 2.5 10 ± 2.3 a20.4 ± 3.1 pmol/mg prt R 14.4 ± 1.7 a,c 16.1 ± 2.3 a 14.3 ± 1.9 a,cGPx S 4.7 ± 0.6 a 6.5 ± 1.3 a 4.6 ± 1.63.9 ± 0.3 nmol NADH/min/mg prtR 3.4 ± 0.5 c 4.3 ± 1.0 c 4.1 ± 1.0The liver of rats fed a high fat diet (HFD) diet without (S)/with (R) Realsilor a standard control diet (controls). Values from controls are reported inthe first column under the parameter. Data are mean ± SD of n = 5 rats pergroup at each time point. a P < 0.05 vs control rats; c P < 0.05 vs rats on HFDdiet without Realsil at the same time point. GPx: Glutathione peroxidase;NADH: Nicotinamide adenine dinucleotide; prt: Protein.relation observed between the circulatory NO derivativesand K-18 levels clearly links NO with the hepatic inflammatoryprocesses occurring under marked liver steatosis.Previous studies have demonstrated elevation of thesemolecules in NAFLD [44] as a consequence of the increasedapoptotic rate due to hepatic inflammation [45] .In the present work, the HFD promoted alterations inmitochondrial complexes, although not deep enough toresult in bioenergetic changes, as reported for other dietmodels including CD [46,47] . Interestingly, the limited arrayof alterations observed in the heart and skeletal musclepoints to the conclusion that this model selectively affectsthe liver.In this scenario, the administration of antioxidantmolecules able to contrast oxidative and nitrosative phenomenaimproved most of the investigated stress parametersboth in the liver and in serum. In fact, in our studythe administration of Realsil was effective in reducing theextent of fatty infiltration of the liver and in modulatingthe changes in mitochondrial function and oxidativeand nitrosative stress both in the liver and in the systemiccirculation. This would suggest that Realsil is effective incontrasting the metabolic alterations resulting in excessfat deposition and at the same time in counteracting theincreased formation of ROS and NO species.WJG|www.wjgnet.com3013 May 28, 2013|Volume 19|Issue 20|
Page 1 and 2: ISSN 1007-9327 (print)ISSN 2219-284
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20 - World Journal of Gastroenterology

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