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7-ketocholesterol and 5,6-secosterol modulate differently the stress-activated mitogen-activated protein kinases (MAPKs) in liver cells.

Abstract
Enhanced oxidative stress is a common feature of liver diseases and contributes to chronic liver disease (CLD) progression by inducing fibrogenesis during liver regeneration. Peroxidation products of cholesterol metabolism, named oxysterols, are new and reliable markers of oxidative stress in vivo. Patients affected by CLDs present high plasma levels of oxysterols, raising the question of the origin and biological relevance of these compounds in the pathophysiology of chronic liver damage. The aim of this study was to examine the molecular basis of the biological effects of oxysterols on liver-derived cells, HepG2 and Huh7. Cells were treated with different concentrations (10(-9) to 10(-5) M) of 7-ketocholesterol used as a reference, and 5,6-secosterol, a recently discovered oxysterol. FACS investigations, caspase-3 activation, and Sytox Green immunofluorescent assay showed that pathological concentrations of oxysterols induced necrosis (30-50%) after 48 h of treatment. The two analyzed compounds displayed a similar, but not identical, behavior. In fact, 5,6-secosterol, but not 7-ketocholesterol, induced cell senescence. Notably, low concentrations of 5,6-secosterol caused a sustained activation of ERK1/2, inducing cell proliferation, this unexpected behavior should be better characterized by further studies. Since enhanced oxidative stress is known to worsen liver chronic hepatitis and frequently results in overall decreased cellular survival, our data suggest the important and different role oxysterols may have in interfering with physiological liver tissue regeneration in injured human liver. Antioxidant treatment may provide a highly specific and effective mean to counteract the common consequences of oxidative stress on chronic hepatitis, such as fibrosis/cirrhosis and liver failure.
AuthorsSimona Anticoli, Mario Arciello, Adriano Mancinetti, Massimo De Martinis, Lia Ginaldi, Luigi Iuliano, Clara Balsano
JournalJournal of cellular physiology (J Cell Physiol) Vol. 222 Issue 3 Pg. 586-95 (Mar 2010) ISSN: 1097-4652 [Electronic] United States
PMID19937729 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • 5,6-secosterol
  • Ketocholesterols
  • Protein Kinase Inhibitors
  • Sterols
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • CASP3 protein, human
  • Caspase 3
  • 7-ketocholesterol
Topics
  • Apoptosis
  • Caspase 3 (metabolism)
  • Cell Cycle
  • Cell Proliferation
  • Cellular Senescence
  • Enzyme Activation
  • Hep G2 Cells
  • Hepatocytes (drug effects, enzymology, pathology)
  • Humans
  • JNK Mitogen-Activated Protein Kinases (metabolism)
  • Ketocholesterols (metabolism)
  • Mitogen-Activated Protein Kinase 1 (metabolism)
  • Mitogen-Activated Protein Kinase 3 (metabolism)
  • Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)
  • Necrosis
  • Oxidative Stress (drug effects)
  • Phosphorylation
  • Protein Kinase Inhibitors (pharmacology)
  • Sterols (metabolism)
  • Time Factors
  • p38 Mitogen-Activated Protein Kinases (metabolism)

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