Hepatic steatosis, the first step in the progression of nonalcoholic fatty liver disease, is characterized by triglyceride accumulation in hepatocytes and is highly prevalent in people with obesity. Although initially asymptomatic, hepatic steatosis is an important risk factor for the development of hepatic insulin resistance and type 2 diabetes mellitus and can also progress to more severe pathologies such as nonalcoholic steatohepatitis, liver fibrosis and cirrhosis; hepatic steatosis has, therefore, received considerable research interest in the past 20 years. The lipid accumulation that defines hepatic steatosis disturbs the function of the endoplasmic reticulum (ER) in hepatocytes, thereby generating chronic ER stress that interferes with normal cellular function. Although ubiquitous stress response mechanisms (namely, ER-associated degradation, unfolded protein response and autophagy) are the main processes for restoring cellular proteostasis, these mechanisms are unable to alleviate ER stress in the context of the fatty liver. Furthermore, ER stress and ER stress responses can promote lipid accumulation in hepatocytes in a counter-productive manner and could, therefore, be the origin of a vicious pathological cycle.
Background: Human dermal fibroblasts (HDF) can be used as a cellular model relatively easily and without genetic engineering. Therefore, HDF represent an interesting tool to study several human diseases including psychiatric disorders. Despite major depressive disorder (MDD) being the second cause of disability in the world, the efficacy of antidepressant drug (AD) treatment is not sufficient and the underlying mechanisms of MDD and the mechanisms of action of AD are poorly understood. Objective: The aim of this review is to highlight the potential of HDF in the study of cellular mechanisms involved in MDD pathophysiology and in the action of AD response. Methods: The first part is a systematic review following PRISMA guidelines on the use of HDF in MDD research. The second part reports the mechanisms and molecules both present in HDF and relevant regarding MDD pathophysiology and AD mechanisms of action. Results: HDFs from MDD patients have been investigated in a relatively small number of works and most of them focused on the adrenergic pathway and metabolism-related gene expression as compared to HDF from healthy controls. The second part listed an important number of papers demonstrating the presence of many molecular processes in HDF, involved in MDD and AD mechanisms of action. Conclusion: The imbalance in the number of papers between the two parts highlights the great and still underused potential of HDF, which stands out as a very promising tool in our understanding of MDD and AD mechanisms of action.
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