Interactions of Perilipin-5 (Plin5) with Adipose Triglyceride Lipase

Abstract

Regulation of triglyceride storage and mobilization is critically dependent on the subcellular targeting and trafficking of specific proteins. Recent work demonstrates that this trafficking involves scaffold proteins of the perilipin (Plin) 2 family, including those that are ubiquitously expressed, such as Plin2 (adipose differentiation-related protein) and Plin3 (tail-interacting protein 47, TIP47), and those with restricted expression, such as Plin1 (perilipin) and Plin5 (muscle lipid droplet protein) that appear to have specialized functions (1). Although each Plin homolog has a conserved Plin domain (pfam 03036), amino acid sequences of family members diverge widely outside of this domain (2). Nonetheless, the sequences of individual orthologs are well conserved in mammals and suggest that important functions might be mediated by sequences outside of the Plin domain.We have been investigating how Plin family members organize and regulate the trafficking of lipolytic effector proteins and have focused on Plin1 and Plin5 (3-6). Plin1 is expressed almost exclusively in adipose tissues and plays a central role in the storage of triglyceride and in the rapid mobilization of fatty acids by activators of protein kinase A (1). Recent work indicates that one means by which Plin1 regulates triglyceride storage and mobilization is by controlling the availability of ␣-␤-hydrolase domain-containing 5 (Abhd5), a potent activator of adipose triglyceride lipase (Atgl) (4).In contrast, Plin5 is highly expressed in tissues that have high rates of fatty acid oxidation, such as heart, skeletal muscle, and liver (7,8). Interestingly, expression of Plin5 promotes both triglyceride storage and fatty acid oxidation. Plin5 expression is up-regulated by peroxisome proliferator-activated receptor ␣, and this regulation appears to be part of an expression program that shifts the metabolism of cells from fatty acid storage to oxidation (7).Lipolysis occurs on the surface of intracellular lipid droplets, and several lines of evidence indicate that droplet targeting is critical to the cellular function of Abhd5 and Atgl (9, 10). Abhd5 is targeted to lipid droplets via direct interactions with Plin1 and Plin5 (5, 10, 11). However, unlike Plin1, Plin5 expression promotes the colocalization and interaction of Abhd5 and Atgl in unstimulated cells, which facilitates lipolysis (3-5). It is not known how Plin5 coordinates the interaction of Atgl and Abhd5. On the one hand, Plin5 could bind Atgl5 directly. Alternatively, Atgl might be recruited to the Plin5-containing lipid droplets by virtue of its interaction with Abhd5.In the experiments below, we determined that Atgl interacts with Plin5 but not Plin1. Interestingly, although Plin5 binds both Abhd5 and Atgl, the same Plin5 molecule does not bind both at the same time. Protein complementation experiments, however, indicate that Plin5 forms homo-oligomers and suggest that Abhd5 and Atgl interact as part of this oligomeric structure. Analysis of chimeric and truncated Plin proteins demonstrates ...

Perilipin 5 restores the formation of lipid droplets in activated hepatic stellate cells and inhibits their activation

“…44 Abhd5 in cytosol is directed to LDs by LD proteins. 41 Interruption of their interactions could greatly affect the activity of ATGL. 40 Mutations of either abhd5 or ATGL result in ectopic lipid accumulation in skin, muscle, and liver.…”

“…53 At the molecular level, independent work from groups strongly supports the idea that Plin5 plays as a scaffold for three major key lipolytic players: abhd5, ATGL, and HSL in hydrolysis of TG in LDs. [40][41][42][43] It has been shown that the C-terminus of Plin5 serves as an ATGL and abhd5 binding domain. 54 ATGL and abhd5 competitively bind Plin5.…”

“…54 ATGL and abhd5 competitively bind Plin5. 41 The interaction between abhd5 and Plin5 is dynamic and essential for regulating the activity of ATGL at LDs. 40 Activation of protein kinases has shown its roles in modulating lipid homeostasis.…”

Perilipins 2 and 3 lack a carboxy-terminal domain present in perilipin 1 involved in sequestering ABHD5 and suppressing basal lipolysis

“…Our studies focused on perilipins 2 and 3, because perilipin 4 is a much longer protein (1,357aa compared with perilipin 1, which has 522 aa in humans) with a very distinct domain architecture, and perilipin 5 has already been shown to bind both ABHD5 and ATGL in a mutually exclusive manner (25)(26)(27).…”

The role of triacylglycerol in cardiac energy provision

“…ATGL overexpression maintained cardiac energetics (ATP; PCr:ATP) and function in high fat fed mice, but exogenous NEFA oxidation was halved, suggesting preferential utilisation of endogenous lipids from the mTAG pool [139]. Perilipin-5 (PLIN5) binds ATGL on the LD surface [140], shielding TAG from lipolysis; ectopic PLIN5 expression increased mTAG levels and decreased FA oxidation, again suggesting rates of FA oxidation may be determined by mTAG-FA turnover [141,142]. PLIN5 is also present on mitochondria, where it facilitates the tightly-coupled association of mitochondria with…”