Plin5, a New Target in Diabetic Cardiomyopathy

Abstract

Abnormal lipid accumulation is commonly observed in diabetic cardiomyopathy (DC), which can create a lipotoxic microenvironment and damage cardiomyocytes. Lipid toxicity is an important pathogenic factor due to abnormal lipid accumulation in DC. As a lipid droplet (LD) decomposition barrier, Plin5 can protect LDs from lipase decomposition and regulate lipid metabolism, which is involved in the occurrence and development of cardiovascular diseases. In recent years, studies have shown that Plin5 expression is involved in the pathogenesis of DC lipid toxicity, such as oxidative stress, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and insulin resistance (IR) and has become a key target of DC research. Therefore, understanding the relationship between Plin5 and DC progression as well as the mechanism of this process is crucial for developing new therapeutic approaches and exploring new therapeutic targets. This review is aimed at exploring the latest findings and roles of Plin5 in lipid metabolism and DC-related pathogenesis, to explore possible clinical intervention approaches.

Figure 1

The process of lipid metabolism in DC. FFAs in cells synthesize TG under the action of Acyl-coA, DPAT, AGPAT, Lipin, and DGAT protein and store TG in LD. With the increase of TG synthesis, LD increases gradually and is separated from ER into cytoplasm to isolate FAs and reduce lipid toxicity. When stimulated by external stimuli, Plin5 recruits ATGL to LD, Plin5 is phosphorylated and inactivated, CGI-58 is released, ATGL and HSL are activated, and lipolysis is initiated. Under the action of corresponding proteases, TG is decomposed into FA, which is released into cytoplasm by FABP4 or directly into mitochondria through Plin5-mediated LD-mitochondrial contact. Meanwhile, Plin5 can carry muFAs into the nucleus. Plin5 binds to SIRT1 PGC-1α to form a complex that activates PPAR and oxidative gene expression, promoting lipolysis and mitochondrial β-oxidation.

Figure 2

The lipid metabolism mechanism of Plin5 in DC. In oxidized tissues and adipocytes, Plin5 mainly regulates fatty acid metabolism through the MAPK pathway, PGC-1 α/PPAR pathway, and PI3K pathway. In pancreatic cells, Plin5 interferes with the PI3K pathway, GPR40 signaling pathway, and IRS-1 phosphorylation pathway to achieve its effect on pancreatic cells. When FA metabolism is disturbed, Plin5 can reduce the microvascular damage, myocardial hypertrophy, myocardial fibrosis, apoptosis/proliferation caused by FA by coordinating the mechanism of mitochondrial damage, oxidative stress, inflammation, insulin resistance, and ER stress.