Hypercholesterolemia increases and exacerbates stress signals leading also to liver damage (LD) and failure. Sirtuin1 (
SIRT1) is involved in lifespan extension and it plays an essential role in hepatic lipid metabolism. However, its involvement in liver hypercholesterolemic damage is not yet completely defined. This in vivo study evaluated the role of
SIRT1 in the hypercholesterolemic-related LD and, then, investigated how oral supplementation of
melatonin, pleiotropic indoleamine, may be protective. Control mice and
apolipoprotein E-deficient mice (
ApoE-/-) of 6 and 15 weeks of age were treated or not treated with
melatonin at the dose of 10 mg/kg/day for 9 weeks. In this study, we evaluated serum
biochemical markers, liver
SIRT1 expression, and oxidative stress markers. We observed that
hypercholesterolemia increased significantly serum
cholesterol and
triglycerides, reduced significantly liver
SIRT1, and, in turn, induced hepatic oxidative stress in untreated
ApoE-/- mice with respect to control mice. Interestingly,
melatonin treatment improved serum
biochemical markers and hepatic morphological impairment and inhibited oxidative stress through its
antioxidant properties and also by
SIRT1 upregulation. In summary,
melatonin oral supplementation may represent a new protective approach to block hypercholesterolemic liver alterations involving also a SIRT1-dependent mechanism.