title: Silybin exerts antioxidant effects and induces mitochondrial biogenesis in liver of rat with secondary biliary cirrhosis.
abstract: The accumulation of toxic hydrophobic bile acids in hepatocytes, observed during chronic cholestasis, induces substantial modification in the redox state and in mitochondrial functions. Recent reports have suggested a significant role of impaired lipid metabolism in the progression of chronic cholestasis. In this work we report that changes observed in the expression of the lipogenic enzymes acetyl-CoA carboxylase and fatty acid synthase were associated with a decrease in the activity of citrate carrier (CIC), a protein of the inner mitochondrial membrane closely related to hepatic lipogenesis. We also verified that the impairment of citrate transport was dependent on modification of the phospholipid composition of the mitochondrial membrane and on cardiolipin oxidation. Silybin, an extract of silymarin with antioxidant and anti-inflammatory properties, prevented mitochondrial reactive oxygen species (ROS) production, cardiolipin oxidation, and CIC failure in cirrhotic livers but did not affect the expression of lipogenic enzymes. Moreover, supplementation of silybin was also associated with mitochondrial biogenesis. In conclusion, we demonstrate that chronic cholestasis induces cardiolipin oxidation that in turn impairs mitochondrial function and further promotes ROS production. The capacity of silybin to limit mitochondrial failure is part of its hepatoprotective property.
authors.affiliation: Centro CURE, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Serviddio
authors.affiliation: Centro CURE, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Bellanti
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Stanca
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Lunetti
authors.affiliation: Centro CURE, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Blonda
authors.affiliation: Centro CURE, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Tamborra
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Siculella
authors.affiliation: Centro CURE, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Vendemiale
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy. Electronic address: loredana.capobianco@unisalento.it.
authors.forename: Loredana
authors.initials: L
authors.lastname: Capobianco
authors.affiliation: Centro CURE, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy. Electronic address: anna.giudetti@unisalento.it.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Giudetti
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000096:biosynthesis; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D000975:Antioxidants / Q000627:therapeutic use*; D001692:Biological Transport; D002308:Cardiolipins / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002779:Cholestasis / Q000188:drug therapy / Q000473:pathology*; D019343:Citric Acid / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics; D004789:Enzyme Activation; D054890:Fatty Acid Synthase, Type I / Q000096:biosynthesis; D022781:Hepatocytes / Q000378:metabolism; D050356:Lipid Metabolism / Q000502:physiology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008105:Liver Cirrhosis, Biliary / Q000188:drug therapy / Q000473:pathology*; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D063269:Mitochondrial Turnover / Q000502:physiology*; D010084:Oxidation-Reduction; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010743:Phospholipids / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077385:Silybin; D012838:Silymarin / Q000627:therapeutic use*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D002308:Cardiolipins; D002352:Carrier Proteins; D004272:DNA, Mitochondrial; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010743:Phospholipids; C501429:Ppargc1a protein, rat; D017382:Reactive Oxygen Species; D012838:Silymarin; D014157:Transcription Factors; C020723:citrate-binding transport protein; D019343:Citric Acid; D000077385:Silybin; D054890:Fatty Acid Synthase, Type I; D000103:Acetyl-CoA Carboxylase
keywords: Citrate carrier; Free radicals; Lipogenic enzymes; Mitochondrial biogenesis; Peroxisome proliferator-activated receptor coactivator-1α; Secondary biliary cirrhosis