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

Abstract

Alcoholic liver disease is the most prevalent chronic liver disease. Melatonin is known to control many vital processes. Here, we explored a novel molecular mechanism by which melatonin‐induced SIRT1 signaling protects against alcohol‐mediated oxidative stress and liver injury. Gene expression profiles and metabolic changes were measured in liver specimens of mice and human subjects. Expression levels of Cb1r, Crbn, Btg2, Yy1, pro‐inflammatory cytokines, and Cyp2e1 were significantly enhanced in chronic alcohol‐challenged mice and human subjects. Levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), hepatic CYP2E1 protein, and reactive oxygen species (ROS) were elevated in alcohol‐fed WT mice but not in Cb1r antagonist‐treated, Crbn null, or Yy1‐silenced mice. Importantly, alcohol‐induced Yy1 and Cyp2e1 expression, ROS amount, and liver injury were markedly diminished by melatonin treatment and the transduction of Sirt1 in mice, whereas this phenomenon was prominently ablated by silencing of Sirt1. Notably, SIRT1 physically interacted with YY1 and attenuated YY1 occupancy on the Cyp2e1 gene promoter. Melatonin‐SIRT1 signaling ameliorates alcohol‐induced oxidative liver injury by disrupting the CRBN‐YY1‐CYP2E1 signaling pathway. The manipulation of CRBN‐YY1‐CYP2E1 signaling network by the melatonin‐SIRT1 pathway highlights a novel entry point for treating alcoholic liver disease.

Kaempferol suppresses acetaminophen-induced liver damage by upregulation/activation of SIRT1

“…Also, SIRT1 deacetylates and inactivates NF-jB p65, which normally stimulates inflammation by upregulation of inflammatory cytokines and induces apoptosis by upregulation of Bax and inhibition of Bcl-2 (Matsuzawa et al 2002;Chong et al 2012). Of note, a very recent study showed that melatonininduced activation of SIRT1 protected against ethanol-induced liver damage mainly through downregulating of hepatic CYP2E1 (Lee et al 2020), thus suggesting that the expression of CYP2E1 is controlled by SIRT1. As expected, the liver of APAP-treated rats of this study showed low expression and activation of SIRT1 with a concomitant increase in the expression of CYP2E1, PARP1 and acetylation of p53, NF-jB p65 and FOXO-1.…”

Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury

“…Subchronic alcohol intake also decreased the levels of SIRT1 and PGC-1α and other isoforms 286 , 287 . Thus, activation of SIRT1 by resveratrol and its synthetic structural derivatives 288 , 289 and melatonin 290 may prevent adduct formation and AGE-associated disease conditions. Furthermore, consumption of anti-inflammatory antioxidants from natural dietary supplements 279 , 281 , 282 , 290 and/or synthetic origins 199 can help reduce the incidence and severity of AGE-associated inflammation and related disorders.…”

“…Thus, activation of SIRT1 by resveratrol and its synthetic structural derivatives 288 , 289 and melatonin 290 may prevent adduct formation and AGE-associated disease conditions. Furthermore, consumption of anti-inflammatory antioxidants from natural dietary supplements 279 , 281 , 282 , 290 and/or synthetic origins 199 can help reduce the incidence and severity of AGE-associated inflammation and related disorders. Furthermore, soluble RAGE 119 , 200 , inhibitors of the RAGE signaling pathway 130 , 131 , neutralizing antibodies against RAGE 57 or AA-AGE adduct 199 , and other AGE-degrading compound(s), such as pyridoxamine and ALT-711 200 , lipoic acid 291 , synthetic compounds OPB-9195 292 , and nitrothiadiazolo[3,2-α]pyrimidines 293 , have been reported to decrease AGE adduct formation.…”

Protective effect of Salidroside on hypoxia‐related liver oxidative stress and inflammation via Nrf2 and JAK2/STAT3 signaling pathways

“…CYP2E1 is one of the main members of CYP450 family, mainly present in liver microsomes and plays a vital role in ROS production and liver injury (Lee et al., 2020 ). Nrf2 is considered as a master regulator that controls the cellular redox state under harmful stresses (Bellezza et al., 2018 ).…”