Exogenous Melatonin Corrects Hepatic Nocturnin Levels in Experimentally Induced MASLD

Melatonin, a neurohormone, improves hepatic function in diet and/or chronodisruption in Metabolic dysfunction Associated with Steatotic Liver Disease (MASLD). Nocturnin (Noct), a circadian clock output gene, putatively regulates hepatic lipid metabolism but the underlying mechanisms related to its regulation remain largely unknown. Herein, we hypothesise that melatonin-mediated improvement in liver function in MASLD is regulated via Noct and this study delves into Noct as a putative target of melatonin. Molecular docking studies (Autodock, Pyrx and PyMol) confirmed interactions between melatonin and mouse Noct (Binding affinity: -7kcal/mol; RMSD: 0). Further, studies on C57BL/6J mice comprised of experimental groups viz. high-fat-high-fructose (H) diet fed, photoperiodic shifts-induced chronodisruption (CD) or a combination of the two (HCD) wherein melatonin-mediated improvements in serum lipid profile (TGs, total lipids, VLDL-chol., LDL-chol. and total cholesterol) and liver function markers (ALT and AST) were recorded. Further, the fatty manifestations, hepatocyte ballooning, and steatotic score were significantly improved following exogenous melatonin. Likewise, the liver samples of H, CD and HCD mice recorded a marked increment in hepatic Noct mRNA expression whereas melatonin administration accounted for a significant improvement in the said expression. These findings were further validated in vitro in HepG2 cells treated with Oleic Acid (OA) cells wherein, melatonin supplementation improved Noct mRNA and protein expressions compared to the disease control. Taken together, this study provides insight into melatonin-mediated modulation in hepatic Noct that correlates with improved hepatic health in experimental models of MASLD.