Melatonin Modulation of Sirtuin-1 Attenuates Liver Injury in a Hypercholesterolemic Mouse Model

Abstract

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.

Induction of SIRT1 by melatonin improves alcohol‐mediated oxidative liver injury by disrupting the CRBN‐YY1‐CYP2E1 signaling pathway

“…It is confirmed for the first time in this study that melatonin‐induced SIRT1 expression modulates alcohol‐mediated target gene expressions and oxidative stress in mouse livers. Indeed, our findings demonstrated that melatonin enhanced SIRT1 expression, which is consistent with previous reports . Notably, melatonin declined alcohol‐mediated elevation of CYP2E1 activity and ROS generation by promoting SIRT1 and reducing YY1‐CYP2E1 expression.…”

“…Indeed, our findings demonstrated that melatonin enhanced SIRT1 expression, which is consistent with previous reports. 14,18,19 Notably, melatonin declined alcohol-mediated elevation of CYP2E1 activity and ROS generation by promoting SIRT1 and reducing YY1-CYP2E1 expression. Likewise, the increase in pro-inflammatory cytokines, ALT, AST, TG, and CHO levels and hepatic steatosis in response changes.…”

“…12,13,29 Several previous studies have demonstrated that melatonin controls cadmium-, hypercholesterolemia-, dimethylnitrosamine-, and endotoxin-mediated oxidative liver injury by controlling several transcriptional regulators (SIRT1, PGC-1α, Nrf2, NF-κB) both in vitro and in vivo. 18,19,30,31 However, the correlation between oxidative liver injury and the protective role of melatonin in alcohol-fed mice had not been investigated.…”

“…SIRT1 regulates a variety of important metabolic processes by interacting and deacetylating several nuclear receptors, transcription factors and cofactors, such as PPARα, forkhead box‐type O1 (FOXO1), nuclear factor‐ κ B (NF‐ κ B), sterol regulatory element binding protein‐1c (SREBP‐1c), and PGC‐1 . Recent studies report the protective role of melatonin in cadmium‐induced hepatotoxicity and in hypercholesterolemia‐mediated liver damage by controlling a SIRT1‐dependent pathway . However, the action of melatonin‐SIRT1 pathway on alcohol‐mediated hepatic injury remains unexplored.…”

“…15,17 Recent studies report the protective role of melatonin in cadmium-induced hepatotoxicity and in hypercholesterolemia-mediated liver damage by controlling a SIRT1-dependent pathway. 18,19 However, the action of melatonin-SIRT1 pathway on alcohol-mediated hepatic injury remains unexplored.…”