A silybin-phospholipid complex prevents mitochondrial dysfunction in a rodent model of nonalcoholic steatohepatitis.
Mitochondrial dysfunction and oxidative stress are determinant events in the pathogenesis of nonalcoholic steatohepatitis. Silybin has shown antioxidant, anti-inflammatory, and antifibrotic effects in chronic liver disease. We aimed to study the effect of the silybin-phospholipid complex (SILIPHOS) on liver redox balance and mitochondrial function in a dietary model of nonalcoholic steatohepatitis. To accomplish this, glutathione oxidation, mitochondrial oxygen uptake, proton leak, ATP homeostasis, and H(2)O(2) production rate were evaluated in isolated liver mitochondria from rats fed a methionine- and choline-deficient (MCD) diet and the MCD diet plus SILIPHOS for 7 and 14 weeks. Oxidative proteins, hydroxynonenal (HNE)- and malondialdehyde (MDA)-protein adducts, and mitochondrial membrane lipid composition were also measured. Treatment with SILIPHOS limited glutathione depletion and mitochondrial H(2)O(2) production. Moreover, SILIPHOS preserved mitochondrial bioenergetics and prevented mitochondrial proton leak and ATP reduction. Finally, SILIPHOS limited the formation of HNE- and MDA-protein adducts. In conclusion, SILIPHOS is effective in preventing severe oxidative stress and preserving hepatic mitochondrial bioenergetics in nonalcoholic steatohepatitis induced by the MCD diet. The modifications of mitochondrial membrane fatty acid composition induced by the MCD diet are partially prevented by SILIPHOS, conferring anti-inflammatory and antifibrotic effects. The increased vulnerability of lipid membranes to oxidative damage is limited by SILIPHOS through preserved mitochondrial function.
Serviddio
Gaetano
G
Centre for the Study of Liver Diseases, Institute of Internal Medicine, Department of Medical and Occupational Sciences, University of Foggia, Foggia, Italy. g.serviddio@unifg.it
Bellanti
Francesco
F
Giudetti
Anna Maria
AM
Gnoni
Gabriele Vincenzo
GV
Petrella
Antonio
A
Tamborra
Rosanna
R
Romano
Antonino Davide
AD
Rollo
Tiziana
T
Vendemiale
Gianluigi
G
Altomare
Emanuele
E
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D004734:Energy Metabolism; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology; D005978:Glutathione / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D015227:Lipid Peroxidation; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008563:Membrane Lipids / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000502:physiology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D010743:Phospholipids / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D000077385:Silybin; D012838:Silymarin / Q000737:chemistry / Q000494:pharmacology
D008563:Membrane Lipids; D010743:Phospholipids; D012838:Silymarin; D000077385:Silybin; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D005978:Glutathione