Melatonin ameliorates simulated‐microgravity‐induced mitochondrial dysfunction and lipid metabolism dysregulation in hepatocytes

The liver is an essential multifunctional organ, which constantly communicates with nearly all tissues. It has raised the concern that microgravity exposure can lead to liver dysfunction and metabolic syndromes. However, molecular mechanisms and intervention measures of the adverse effects of microgravity on hepatocytes are limited. In this study, we utilized the random positioning machine culture system to investigate the adverse effects on hepatocytes under simulated microgravity (SMG). Our results showed that SMG impaired hepatocyte viability, causing cell cycle arrest and apoptosis. Compared to normal gravity, it also triggered lipid accumulation, elevated triglyceride (TG) and ROS levels, and impaired mitochondria function in hepatocytes. Furthermore, RNA sequencing results showed that SMG upregulated genes implicated in lipid metabolisms, including PPARγ, PLIN2, CD36, FABPs, etc. Importantly, all these defects can be suppressed by melatonin, a potent antioxidant secreted by the pineal gland, suggesting its potential use of therapeutic intervention. Melatonin reduces SMG‐induced cellular ROS production, restores mitochondria respiration, and suppresses the expression of genes involved in TG synthesis, e.g., PPARγ and PLIN2, thereby reducing lipid droplet formation. In addition, it suppresses fatty acid intake, down‐regulates FABPs and CD36, mitigates apoptosis, and reduces CPT1a. Hence, the antioxidative effect of melatonin mitigates SMG‐mediated detrimental effects in hepatocytes.