Perilipin 5 Protects against Cellular Oxidative Stress by Enhancing Mitochondrial Function in HepG2 Cells

Abstract

Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide. Reactive oxygen species (ROS), as potent oxidants in cells, have been shown to promote the development of NAFLD. Previous studies reported that for ROS-induced cellular oxidative stress, promoting lipid droplet (LD) accumulation is associated with the cellular antioxidation process. However, the regulatory role of LDs in relieving cellular oxidative stress is poorly understood. Here, we showed that Perilipin 5 (PLIN5), a key LD protein related to mitochondria–LD contact, reduced ROS levels and improved mitochondrial function in HepG2 cells. Both mRNA and protein levels of PLIN5 were significantly increased in cells with hydrogen peroxide or lipopolysaccharide (LPS) treatment (p < 0.05). Additionally, the overexpression of PLIN5 promoted LD formation and mitochondria–LD contact, reduced cellular ROS levels and up-regulated mitochondrial function-related genes such as COX and CS. Knockdown PLIN5, meanwhile, showed opposite effects. Furthermore, we identified that cellular oxidative stress up-regulated PLIN5 expression via the JNK-p38-ATF pathway. This study shows that the up-regulation of PLIN5 is a kind of survival strategy for cells in response to stress. PLIN5 can be a potential therapeutic target in NAFLD.

Perilipin 5 Reduces Oxidative Damage Associated With Lipotoxicity by Activating the PI3K/ERK-Mediated Nrf2-ARE Signaling Pathway in INS-1 Pancreatic β-Cells

“…While this is the first study to demonstrate the relationship between Plin5 and oxidative stress in pancreatic β-cells, it is not surprising as Plin5 has been reported to be an important factor in maintaining cellular metabolic homeostasis during various kinds of stress and negatively associated with oxidative stress in non-insulin-secreting cells (21,23,24,44). Indeed, in HepG2 cells, overexpression of Plin5 protects against hydrogen peroxide or lipopolysaccharide induced cellular oxidative stress (44). In mouse hearts, Plin5 deficiency provokes oxidative stress, leads to exacerbated myocardial ischaemia/reperfusion injury (24).…”

“…However, the exact mechanisms involved in the protective role of Plin5 are not fully understood. There is some limited evidence indicating that Plin5 may enhance the function of mitochondria, an organelle which is responsible for the majority of cellular ROS production (44). By gain-offunction strategy, Plin5 was observed to promote mitochondria-LD contact, up-regulated mitochondria function-related genes and hence enhancing mitochondrial function in HepG2 cells.…”

“…Oxidative stress has been proposed as a common mechanism suggested for disruption of pancreatic β-cell, a process which is critical in the pathophysiology of type 2 diabetes (43). Plin5, a LD protein which is abundantly expressed in tissues with high oxidative capacity, is able to improve the cellular antioxidant capacity of these tissues and in turn partly prevent associated injuries (22)(23)(24)44). Recently, Plin5 has been established as a LD protein important for lipid metabolism and insulin secretion in β-cells (27).…”

“…By gain-offunction strategy, Plin5 was observed to promote mitochondria-LD contact, up-regulated mitochondria function-related genes and hence enhancing mitochondrial function in HepG2 cells. The author concluded that the Plin5-mediated mitochondria-LD contact could be an important mechanism for cells to respond to oxidative stress (44). Similarly, Plin5 overexpression in brown adipose tissue also recruits mitochondria to LD and then increases ATP synthase-dependent triglyceride synthesis coupled with reduced fatty acid oxidation capacity (45).…”

“…The detailed mechanism of the antioxidant role of Plin5 via regulating Nrf2-ARE system in β-cells was explored preliminary in the present study. In some tissues, Plin5 has been reported to involve in the regulation of PI3K/Akt or MAPK pathways (p38 MAPK, ERK, and JNK) (21,24,40,44,49), which is the upstream modulators of Nrf2 in pancreatic β-cells (39,41). As evidenced by prior studies, excess ROS production and oxidative stress results in the activation of apoptotic p38 MAPK and JNK signaling, whereas activation of antiapoptotic PI3K/Akt and ERK pathways facilitates the translocation of Nrf2 into the nucleus, thereby activating the Nrf2/ARE pathway and alleviating oxidative damage (50,51).…”