Effect of Antidepressants on Non-Alcoholic Fatty Liver Disease and their Underlying Mechanism

Introduction: The high prevalence of Non-Alcoholic Fatty Liver Disease (NAFLD), a chronic progressive disease characterized by hepatic steatosis, poses a serious burden to human health. Depression and NAFLD share some common pathogenic mechanisms, and patients with depression are at an increased risk of NAFLD. The drug mirtazapine is commonly used in the treatment of depression, but it can also cause liver damage. However, whether mirtazapine induces or aggravates NAFLD remains uncertain. Thus, we evaluated the risk factors for NAFLD in patients with depression and the effects of mirtazapine on NAFLD in vitro. Methods: Inpatients diagnosed with depression at the Second Xiangya Hospital of Central South University between 2019 and 2022 were included in this study, and NAFLD was determined using an abdominal ultrasound examination. The risk factors for the development of NAFLD in patients with depression were analyzed using logistic regression analysis. AML-12 and MIHA cell lines were used to observe the effects of mirtazapine on NAFLD using oil red O staining. RT-qPCR and western blotting were used to explore the molecular mechanism behind NAFLD development induced by mirtazapine. Results: Logistic regression analysis showed that older age, use of mirtazapine or fluoxetine, longer duration of antidepressant use, and combined hyperlipidemia or T2DM were risk factors for NAFLD in patients with depression. in vitro experiments revealed a subsequent increase in the content of intracellular lipid droplets as mirtazapine concentration increased. Mechanistic studies showed that mirtazapine increased the expressions of TLR4, MyD88, IFN-γ, IL-1β, IL-6, and TNF-α mRNA in hepatocytes. Moreover, the expressions of TLR4, MyD88, and p-NF-κB-p65 proteins increased in a dose-dependent manner. Conclusion: Age, antidepressant type, duration of antidepressant use, and comorbidities could be risk factors for NAFLD in patients with depression. Furthermore, mirtazapine can cause steatosis in both AML-12 and MIHA cell lines and may promote the development of NAFLD through the TLR4/MyD88/NF-κB signaling pathway. This study lays a solid foundation for further research on depression and NAFLD and can contribute to the prevention and treatment of these two diseases. result: Logistic regression analysis showed that older age, use of mirtazapine or fluoxetine, longer duration of antidepressant use, and combined hyperlipidemia or T2DM were risk factors for NAFLD in patients with depression. In vitro experiments revealed a subsequent increase in the content of intracellular lipid droplets as mirtazapine concentration increased. Mechanistic studies showed that mirtazapine increased the expression of TLR4, MyD88, IFN-γ, IL-1β, IL-6, and TNF-α mRNA in hepatocytes and the expression of TLR4, MyD88 and p-NF-κB-p65 proteins in a dose-dependent manner.