Perilipin 5 deficiency promotes atherosclerosis progression through accelerating inflammation, apoptosis, and oxidative stress

Abstract

Excessive plasma triglyceride (TG) and cholesterol levels promote the progression of several prevalent cardiovascular risk factors, including atherosclerosis, which is a leading death cause. Perilipin 5 (Plin5), an important perilipin protein, is abundant in tissues with very active lipid catabolism and is involved in the regulation of oxidative stress. Although inflammation and oxidative stress play a critical role in atherosclerosis development, the underlying mechanisms are complex and not completely understood. In the present study, we demonstrated the role of Plin5 in high‐fat‐diet‐induced atherosclerosis in apolipoprotein E null (ApoE−/−) mice. Our results suggested that Plin5 expressions increased in the artery tissues of ApoE−/− mice. ApoE/Plin5 double knockout (ApoE−/−Plin5−/−) exacerbated severer atherogenesis, accompanied with significantly disturbed plasma metabolic profiles, such as elevated TG, total cholesterol, and low‐density lipoprotein cholesterol levels and reduced high‐density lipoprotein cholesterol contents. ApoE−/−Plin5−/− exhibited a higher number of inflammatory monocytes and neutrophils, as well as overexpression of cytokines and chemokines linked with an inflammatory response. Consistently, the IκBα/nuclear factor kappa B pathway was strongly activated in ApoE−/−Plin5−/−. Notably, apoptosis was dramatically induced by ApoE−/−Plin5−/−, as evidenced by increased cleavage of Caspase‐3 and Poly (ADP‐ribose) polymerase‐2. In addition, ApoE−/−Plin5−/− contributed to oxidative stress generation in the aortic tissues, which was linked with the activation of phosphatidylinositol 3‐kinase/protein kinase B and mitogen‐activated protein kinases pathways. In vitro, oxidized low‐density lipoprotein (ox‐LDL) increased Plin5 expression in RAW264.7 cells. Its knockdown enhanced inflammation, apoptosis, oxidative stress, and lipid accumulation, while promotion of Plin5 markedly reduced all the effects induced by ox‐LDL in cells. These studies strongly supported that Plin5 could be a new regulator against atherosclerosis, providing new insights on therapeutic solutions.

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

“…In line with our data in pancreatic β-cells, livers of mice with liver-specific Plin5 ablation exhibited activation of JNK and Plin5-null cardiomyocytes showed decreased phosphorylation of PI3K/Akt (24,40). However, in the aortic tissues, ApoE/Plin5 double knockout linked with the activation of PI3K/Akt and MAPK pathways, therefore, may contribute to oxidative stress generation (21). The reason of discordant results is not well known, the induction of PI3K/Akt and MAPK pathways by ApoE deletion per se may complicate the study of the regulation of Plin5 in these signaling pathways and tissue-specific role of Plin5 in different target tissues may also be considered.…”

“…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).…”

“…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).…”

“…In the aortic tissues, heart and liver, Plin5 has been reported to associate with PI3K/Akt or MAPK pathway (p38 MAPK, ERK, and JNK) (21,24,40), which involve in modulating oxidative stress (41,42). Here, we first investigated the protein expressions of p-Akt, p-p38, p-ERK1/2, and p-JNK in INS-1 cells incubated with palmitate.…”

“…Among these, Perilipin 5 (Plin5) is mainly expressed in tissues with very active lipid catabolism, including heart, brown adipose tissue, skeletal muscle, and liver and promotes LD accumulation but inhibits lipolysis by interacting with lipases such as ATGL, Abhd5 and CGI-58 (16)(17)(18)(19)(20). By modulating lipid homeostasis, Plin5 plays a role in ameliorating oxidative stress-induced damage in heart, skeletal muscle, hepatic stellate cells and aortic valve tissues (21)(22)(23)(24)(25). However, the regulation of Plin5 in FFA-induced oxidative stress and oxidant damage in pancreatic β-cells, to our knowledge, is not established until now.…”