Psoriasis is a common chronic inflammatory skin disease that affects approximately 3% of the population worldwide. The phenotype of psoriasis is characterized by the development of erythematous papules and overlying scaly plaques [1]. Psoriasis is associated with a variety of factors, including innate and adaptive immune responses, genetic factors, environmental factors and metabolic disorders [2]. Beyond the skin, psoriasis is often associated with comorbidities such as metabolic syndrome [3]. A retrospective study has shown that the incidence of metabolic syndrome in patients with psoriasis is much higher than that in healthy people. Psoriasis is a chronic systemic inflammatory skin disease associated with dyslipidemia [4]. Significantly abnormal lipid metabolism is shown by patients with psoriasis. Elevated cholesterol, triglyceride, and low-density lipoprotein (LDL) levels can accelerate the adhesion and aggregation of platelets as factors affecting psoriasis [5, 6]. As the underlying mechanism is still unclear, to date, no effective drug for treating psoriasis is available.
Excessive and long-term lipid accumulation can induce oxidative stress in the cell. It has been demonstrated oxidative stress contributes to the development of psoriasis [7]. Impaired antioxidant system, together with excessive reactive oxygen species (ROS) production, is involved in the pathogenesis of psoriasis. External detrimental agents such as cigarette smoking, air pollution, physical damages as well as biological agents (virus, bacteria etc.) can trigger a keratinocytes damages by an overproduction of ROS [8]. Several studies have found there is an increased ROS production in psoriatic skin [7]. Furthermore, it has been demonstrated that Hydrogen peroxide (H2O2) could promote cell proliferation in the tissue regeneration as well as embryonic development [9]. A series of antioxidative enzymes including superoxide dismutase (SOD) and catalase (CAT), comprise the antioxidant defense system, which scavenges excessive ROS to maintain the normal function of the cell. We speculated that in psoriatic skin, the expressions of several antioxidative enzymes decrease, which would be responsible for the increased ROS level. As a consequence, increased ROS may aggravate the psoriasis through stimulating keratinocytes proliferation.
It is well accepted that long-term hyperlipidemia inhibits the autophagy in a series of metabolic diseases. Autophagy is a self-digestion process that occurs in all cells. Basal level of autophagy in a cell helps to maintain its homeostatic state and normal function under stressful conditions. It has widely accepted that autophagy is up-regulated during the early stage of non-alcoholic fatty liver disease (NAFLD) as an attempt to prevent lipid accumulation. However, excessive lipid accumulation in the liver for a long time would block the autophagy process [10]. It has been well established that many therapeutic strategies induce apoptosis through promoting autophagy in tumor cells. Therefore, we speculated that increasing autophagy in free fatty acids (FFA) treated keratinocytes would induce apoptosis and ameliorate psoriasis effectively.
Forkhead box O 3 (FOXO3) is a crucial transcription factor in various biological processes, including development, proliferation, apoptosis, metabolism, and differentiation, by regulating a wide spectrum of genes [11]. It inhibits cell proliferation through transcription of multiple cell cycle kinase inhibitors like p16, p21 and p27. Under more oxidizing conditions, to counteract elevated ROS production in the cell, FOXO3 mediates the transcription of antioxidant genes including CAT and SOD2 [12]. In addition, FOXO3 initiates serval autophagy pathways to repress cell proliferation. In response to the accumulation of stress, FOXO3 may activate both the ubiquitin-proteasome pathway and the transcription of autophagy-related genes such as those encoding LC3 and BNIP3, inducing the formation of autophagy [13]. As these, we speculated that FOXO3 would be an drug target for regulating cell proliferation and apoptosis in psoriasis.
Metformin is utilized as a first-line antidiabetic agent for the treatment of type 2 diabetes mellitus (T2DM), as it has been shown to improve metabolic homeostasis including hyperglycemia and dyslipidemia. Previous studies have demonstrated that the long-term use of metformin is associated with a reduced risk of psoriasis [14, 15]. However, further studies are required to identify the potential mechanism.
In our current study, we demonstrated for the first time that under the hyperlipidemia conditions, metformin suppressed cell proliferation and induced apoptosis in FFA treated human keratinocyte via FOXO3-dependent pathway. Metformin activated the FOXO3 to upregulate expressions of antioxidative enzymes SOD2 and CAT to reduce ROS. Consequently, it would block the proliferation caused by ROS. Meanwhile, FOXO3 activation induced the apoptosis by increasing autophagy. Both of these were responsible for the alleviation of psoriasis under hyperlipidemia.