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Review
. 2023 Aug 7;15(15):4013.
doi: 10.3390/cancers15154013.

Challenges in Pharmacological Intervention in Perilipins (PLINs) to Modulate Lipid Droplet Dynamics in Obesity and Cancer

Victória Bombarda-Rocha  1   2 , Dany Silva  1   2 , Allal Badr-Eddine  1 , Patrícia Nogueira  1   2 , Jorge Gonçalves  1   2 , Paula Fresco  1   2
Affiliations
Review

Challenges in Pharmacological Intervention in Perilipins (PLINs) to Modulate Lipid Droplet Dynamics in Obesity and Cancer

Victória Bombarda-Rocha et al. Cancers (Basel). .

Abstract

Perilipins (PLINs) are the most abundant proteins in lipid droplets (LD). These LD-associated proteins are responsible for upgrading LD from inert lipid storage structures to fully functional organelles, fundamentally integrated in the lipid metabolism. There are five distinct perilipins (PLIN1-5), each with specific expression patterns and metabolic activation, but all capable of regulating the activity of lipases on LD. This plurality creates a complex orchestrated mechanism that is directly related to the healthy balance between lipogenesis and lipolysis. Given the essential role of PLINs in the modulation of the lipid metabolism, these proteins can become interesting targets for the treatment of lipid-associated diseases. Since reprogrammed lipid metabolism is a recognized cancer hallmark, and obesity is a known risk factor for cancer and other comorbidities, the modulation of PLINs could either improve existing treatments or create new opportunities for the treatment of these diseases. Even though PLINs have not been, so far, directly considered for pharmacological interventions, there are many established drugs that can modulate PLINs activity. Therefore, the aim of this study is to assess the involvement of PLINs in diseases related to lipid metabolism dysregulation and whether PLINs can be viewed as potential therapeutic targets for cancer and obesity.

Keywords: cancer; lipid droplets; obesity; perilipins.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Overview of LD biogenesis in cancer cells. The figure illustrates the possible sources of FAs and the mechanisms involved in LD biogenesis: Free FA uptake can occur through FABPpm (1) and, when combined with lipoproteins, uptake occurs through CD36-mediated internalization, through a clathrin-mediated endocytosis (2). These FA scavenging mechanisms may be complemented by FA de novo synthesis (3). The FAs absorbed/synthetized will be esterified into neutral lipids and can be transported to the ER or to LD. TAG synthesis starts with the activation of FA into Acyl-CoA and follows in the ER by action of the esterification enzymes (4). The newly formed neutral lipids accumulate between the ER bilayers, where LD biogenesis occurs. SEIPIN stabilizes the LD structure while FIT proteins help in the portioning of neutral lipids (5). Once fully formed, the LD will be released into the cytosol, carrying a set of proteins and enzymes for managing the lipid cargo in response to lipolytic stimuli (6). Abbreviations: ACS (acyl-CoA synthetase); AGPAT (acylglycerol-P acyltransferase); ATGL (adipose triacylglyceride lipase); CGI-58 (comparative gene identification 58 protein); DAG (diacylglyceride); DGAT (diacylglycerol acyltransferase); FABPpm (plasma membrane fatty acid-binding proteins); FA (fatty acid); FASN (fatty acid synthase); FIT (fat-storage inducing transmembrane); GLUT (glucose transporter); GPAT (glycerol-P acyltransferase); HSL (hormone sensitive lipase); LPA (lysophosphatidic acid); PA (phosphatidic acid); PAP (phosphatidic acid phosphohydrolase); PLIN (perilipin); TAG (triacylglyceride); TCA cycle (tricarboxylic acid cycle).
Figure 2
Figure 2
Influence of PLIN1 activation on the assembly of lipolytic enzymes in the lipid droplet (LD). Panel (A): In basal state, CGI-58 remains attached to PLIN1 avoiding interaction with ATGL and consequent co-activation of the lipase. The lipid content of the LD stays protected from lipolytic activity. Panel (B): In stimulated state, PKA phosphorylates PLIN1 and the interaction with CGI-58 is broken. CGI-58 binds to phosphorylated ATGL, and the lipase is fully activated. Phosphorylated HSL binds to phosphorylated PLIN1, which allows access to the lipid content of the LD. Abbreviations: ATGL (adipose triacylglyceride lipase); CGI-58 (comparative gene identification 58 protein); HSL (hormone sensitive lipase); P (phosphate); PKA (protein kinase A); PLIN1 (perilipin 1).
Figure 3
Figure 3
Influence of PLIN2 activation on the assembly and access of lipolytic enzymes in the lipid droplet (LD). Panel (A): In basal state, PLIN2 stays attached to the LD surface, protecting the LD content from the lipase activity as a barrier. Panel (B): In stimulated state, AMPK phosphorylates PLIN2. Phosphorylated PLIN2 binds to Hsc70 and is subsequently carried to the lysosome for chaperone-mediated autophagy degradation. Without PLIN2, the LD is vulnerable to the lipolytic activity of the lipases. Abbreviations: AMPK (AMP-activated protein kinase); ATGL (adipose triacylglyceride lipase); CGI-58 (comparative gene identification 58 protein); Hsc70 (heat shock cognate 70 kDa protein); HSL (hormone sensitive lipase); P (phosphate); PLIN2 (perilipin 2).
Figure 4
Figure 4
Influence of PLIN5 activation on the assembly and access of lipolytic enzymes in the lipid droplet (LD). Panel (A): In basal state, PLIN5 binds to CGI-58 and ATGL, preventing their interaction and consequent lipolytic activity. Panel (B): In stimulated state, PKA phosphorylates PLIN5 and its interaction with CGI-58 and ATGL is undone. CGI-58 binds to phosphorylated ATGL and the lipase is fully activated. Phosphorylated HSL is active and it keeps bonded to phosphorylated PLIN5, which allows access to the lipid content of the LD. Phosphorylated PLIN5 can also travel to the nucleus, where it binds to sirtuin1 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha to activate the transcription of genes related FA catabolism, mitochondrial biogenesis, and respiration. PLIN5 is also known to be a contact site between LDs and mitochondria during β-oxidation. Abbreviations: ATGL (adipose triacylglyceride lipase); CGI-58 (comparative gene identification 58 protein); HSL (hormone sensitive lipase); P (phosphate); PKA (protein kinase A); PLIN5 (perilipin 5).
Figure 5
Figure 5
PLIN’s coordination of FA storage and possible pharmacological intervention strategies. Increase in the body’s need for FAs for β-oxidation is signaled through hormone-dependent PKA activation, which leads to PKA-mediated lipolysis and increase of β-oxidation to fulfill the body’s energy demands. This mechanism is partly orchestrated by the type of PLIN expressed in each cell type. In adipocytes (Box A), PKA induces PLIN1 phosphorylation, allowing lipolytic action over the lipid droplet (LD) lipid content. In β-oxidative cells (Box B), PKA induces PLIN5 phosphorylation, favoring FA transfer to mitochondria and β-oxidation. Conditions of starvation/nutrient scarcity (low ATP/AMP ratio) are signaled through AMPK. AMPK activation induces PLIN2 phosphorylation, allowing the lipolytic action over the LD lipid content (see text for details). The increase in free FA availability will stimulate PPARs. PPARγ activation in adipocytes will stimulate adipogenesis (preadipocyte differentiation) and expression of PLIN1 and PLIN2, increasing the storage capacity and their capacity to react to hormone-induced FA mobilization. PPARγ activation in β-oxidative cells will increase mainly PLIN2 expression, favoring FA storage in LDs and the capacity of these cells to react to local starvation conditions. Increased FA availability will also activate PPARα, which stimulates PLIN5 expression in β-oxidative cells, increasing their β-oxidative capacity to react to hormone stimulation. Pharmacologically, PPARs, PKA, and AMPK can be modulated by widely used drugs such as TZDs (PPARγ agonists), fibrates (PPARα agonists), metformin (AMPK activator), and adrenoceptor agonists and antagonists (modulation of PKA pathway). In the figure, green lines indicate activation and red lines indicate inhibition. Abbreviations: AMPK (AMP-activated protein kinase); FA (fatty acid); LD (lipid droplet); P (phosphate); PKA (protein kinase A); PLIN1 (perilipin 1); PLIN2 (perilipin 2); PLIN5 (perilipin 5); PPARα (peroxisome proliferator-activated receptor alpha); PPARγ (peroxisome proliferator-activated receptor gamma); TZDs (thiazolidinediones).
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