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.