20 - World Journal of Gastroenterology

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Grattagliano I et al . Silybin and liver steatosisA200B150Normalized band density(% of control)15010050a, ca, caaNormalized band density(% of control)1251007550aa, caaa, c250Day 14 Day 30 Day 600Day 14 Day 30 Day 60C200D200aNormalized band density(% of control)15010050aNormalized band density(% of control)15010050aaa0Day 14 Day 30 Day 600Day 14 Day 30 Day 60EComplexⅤⅢⅣⅡⅠActinCTLDietDiet + RealsilCTLDietDiet + RealsilDay 14 Day 30 Day 60CTLDietDiet + RealsilFigure 4 Western blotting analysis of the components of liver mitochondrial oxidative phosphorylation system in rats receiving high fat diet with (greybar) or without (black bar) Realsil and in control (white bar) rats fed a standard chow-diet. Band density for the target protein normalized for the correspondingβ-actin for A: Respiratory complex Ⅰ; B: Respiratory complex Ⅱ; C: Respiratory complex Ⅳ; D: Respiratory complex Ⅴ; E: Picture representative of Western blottinganalysis. Data are means ± SE of n = 3-4 independent experiments. a P < 0.05 vs control rats; c P < 0.05 vs untreated rats at the same time points.Silybin, the major constituent of milk thistle extract,affords hepatoprotection in vitro and in vivo [48,49] by inhibitingthe production of pro-inflammatory and pro-fibrogenicfactors [12,50] . The conjugation with phospholipidsgreatly increases its intestinal absorption and the systemicbioavailability [51] . However, the mechanisms of the hepatocyteprotection have not been completely defined.Some hypotheses point to a potential antioxidant cytoprotectiveeffect of Realsil by including the modulationof protein oxidation/denitrosation and the maintenanceof membrane lipid composition and function [52] . To demonstratethese effects, we investigated the protective effectsof Realsil on oxidative/nitrosative changes both inthe liver and in circulation.Indeed, although the subtle mechanisms regulatingthe protein nitrosation/denitrosation process havenot been completely identified, it has been shown thatthioredoxin-deficient cells denitrosate nitrosothiols lessefficiently [37] and that nitrosative stress is critically importantin promoting S-nitrosylation and nitration of variousmitochondrial proteins, leading to mitochondrial dysfunction,decreased energy supply, and increased hepatic injury[53] . With ongoing steatosis, the decrement in hepaticthioredoxin and GSH levels we observed may be dueWJG|www.wjgnet.com3014 May 28, 2013|Volume 19|Issue 20|
Grattagliano I et al . Silybin and liver steatosisalso to a down-regulation process associated with excessdeposition of fat and toxic molecules and may indirectlycontribute to the progressive appearance of other oxidativechanges.In our study, Realsil was able to counteract most ofthe oxidative biochemical alterations during the earlyphases of steatosis while it resulted less effective later (30and 60 d) when the extent of fat infiltration was massive.The protection promoted by Realsil is certainly exerted atdifferent levels and particularly at mitochondrial level [54] .The changes (both morphological and biochemical)observed in the liver of rats receiving Realsil were alsoevident at systemic level and this more explicitly relatessystemic with hepatic changes in animals with fatty liver.COMMENTSBackgroundFatty degeneration represents a leading factor of hepatocyte dysfunction and isassociated with excess delivery of stress molecules thus rendering the liver amajor source of systemic alterations in patients with metabolic syndrome. Adaptivemetabolic mechanisms have been described during the early phase of fattyinfiltration including expression of intracellular sensors and signaling moleculesfor lipid metabolism and oxidative stress pathways. Vitamin E efforts a remarkableprotection against lipid oxidation and, if vehicoled within a phospholipidscomplex together with silybin, a silybum marianum extract, protects against profibroticoxidative injury.Research frontiersThe threshold above which fat infiltration becomes dangerous is not clear, sofar. Several observations suggest that ongoing fatty degeneration indeed exposeshepatocytes to higher risk of oxidative damages.Innovations and breakthroughsLittle is known about the effectiveness of vitamin E-silybin-phospholipid complexin blocking or modulating reactive oxygen species/NO production and their oxidanteffects. This study also gives answer to the question whether administrationof an antioxidant complex is able to break off the intracellular mechanismsleading to a progressive accumulation of neutral lipids in fatty hepatocytes andmitochondrial dysfunction.ApplicationsRealsil was able to counteract most of the oxidative hepatic changes during theearly phases of steatosis while it resulted less effective later when the extentof fat infiltration was massive. The changes observed in the rat fatty liver werealso evident at systemic level pointing to a relationship between systemic andhepatic alterations.TerminologyLiver steatosis occurs when the amount of neutral fat exceeds 5% of organweight. Realsil is a compound constituted by vitamin E and silybin complexedwith phospholipids. Silybin is a silybum marianum extract; it is known to protectagainst pro-fibrotic oxidative injury.Peer reviewIn this descriptive study, the authors show that Realsil is able to reduce liverinjury in two different animal models of steatosis. Realsil seems to protect bydecreasing toxic free radicals species as highly delivered by fatty hepatocytes.REFERENCES1 Humphreys D. Careers extraordinary: “what’s on the programmetoday, sister”? Nurs Times 1972; 68: 308-310 [PMID:5015760]2 Portincasa P, Grattagliano I, Palmieri VO, Palasciano G.Nonalcoholic steatohepatitis: recent advances from experimentalmodels to clinical management. Clin Biochem 2005;38: 203-217 [PMID: 15708540 DOI: 10.1016/j.clinbiochem.2004.10.014]3 Grattagliano I, Caraceni P, Calamita G, Ferri D, GarganoI, Palasciano G, Portincasa P. Severe liver steatosis correlateswith nitrosative and oxidative stress in rats. Eur JClin Invest 2008; 38: 523-530 [PMID: 18578693 DOI: 10.1111/j.1365-2362.2008.01963.x]4 Palasciano G, Moschetta A, Palmieri VO, Grattagliano I,Iacobellis G, Portincasa P. Non-alcoholic fatty liver disease inthe metabolic syndrome. Curr Pharm Des 2007; 13: 2193-2198[PMID: 17627552]5 Yang S, Zhu H, Li Y, Lin H, Gabrielson K, Trush MA, DiehlAM. Mitochondrial adaptations to obesity-related oxidantstress. Arch Biochem Biophys 2000; 378: 259-268 [PMID:10860543 DOI: 10.1006/abbi.2000.1829]6 Merriman RB, Aouizerat BE, Bass NM. Genetic influencesin nonalcoholic fatty liver disease. J Clin Gastroenterol 2006;40 Suppl 1: S30-S33 [PMID: 16540764 DOI: 10.1097/01.mcg.0000168643.16074.19]7 Sanyal AJ, Campbell-Sargent C, Mirshahi F, Rizzo WB,Contos MJ, Sterling RK, Luketic VA, Shiffman ML, Clore JN.Nonalcoholic steatohepatitis: association of insulin resistanceand mitochondrial abnormalities. Gastroenterology 2001; 120:1183-1192 [PMID: 11266382]8 Shteyer E, Liao Y, Muglia LJ, Hruz PW, Rudnick DA. Disruptionof hepatic adipogenesis is associated with impairedliver regeneration in mice. Hepatology 2004; 40: 1322-1332[PMID: 15565660 DOI: 10.1002/hep.20462]9 Yamaguchi K, Yang L, McCall S, Huang J, Yu XX, PandeySK, Bhanot S, Monia BP, Li YX, Diehl AM. Inhibiting triglyceridesynthesis improves hepatic steatosis but exacerbatesliver damage and fibrosis in obese mice with nonalcoholicsteatohepatitis. Hepatology 2007; 45: 1366-1374 [PMID:17476695 DOI: 10.1002/hep.21655]10 Trevisani F, Colantoni A, Caraceni P, Van Thiel DH. The useof donor fatty liver for liver transplantation: a challenge or aquagmire? J Hepatol 1996; 24: 114-121 [PMID: 8834034]11 Hu JJ, Roush GC, Berwick M, Dubin N, Mahabir S, ChandiramaniM, Boorstein R. Effects of dietary supplementationof alpha-tocopherol on plasma glutathione and DNA repairactivities. Cancer Epidemiol Biomarkers Prev 1996; 5: 263-270[PMID: 8722217]12 Trappoliere M, Caligiuri A, Schmid M, Bertolani C, FailliP, Vizzutti F, Novo E, di Manzano C, Marra F, Loguercio C,Pinzani M. Silybin, a component of sylimarin, exerts antiinflammatoryand anti-fibrogenic effects on human hepaticstellate cells. J Hepatol 2009; 50: 1102-1111 [PMID: 19398228DOI: 10.1016/j.jhep.2009.02.023]13 Tietze F. Enzymic method for quantitative determination ofnanogram amounts of total and oxidized glutathione: applicationsto mammalian blood and other tissues. Anal Biochem1969; 27: 502-522 [PMID: 4388022]14 Grattagliano I, Russmann S, Palmieri VO, Portincasa P,Palasciano G, Lauterburg BH. Glutathione peroxidase, thioredoxin,and membrane protein changes in erythrocytes predictribavirin-induced anemia. Clin Pharmacol Ther 2005; 78:422-432 [PMID: 16198661 DOI: 10.1016/j.clpt.2005.07.002]15 Slater TF, Sawyer BC. 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Page 3 and 4: Phillip S Oates, PerthRoss C Smith,
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