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

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.

Clinically Effective Molecules of Natural Origin for Obesity Prevention or Treatment

“…Other widely studied alterations include loss-of-function variants of the gene that encodes adenylate cyclase 3, which is widely distributed, predominantly in adipose and subcutaneous tissue, but also participates in the correct functioning of the MC4R gene [ 10 ] and in the synthesis of cyclic adenosine monophosphate (cAMP), which functions as a second messenger in the glucagon-like peptide-1 (GLP-1) signaling pathway, the hormone ghrelin and the melanocortin-stimulating hormone [ 10 ], POMC , Fat Mass and Obesity ( FTO ) [ 11 ], interleukin 6 ( IL-6 ) [ 12 ], perilipin ( PLIN ) [ 13 ], adiponectin ( ADIPOQ ) [ 14 ], LEP [ 15 ], LEPR [ 16 ], POMC [ 17 ] genes, the family of peroxisome proliferator-activated receptors (PPAR) [ 18 ] and the uncoupling proteins (UCPs) [ 19 ], which are related to the activation of thermogenesis. These genes and their metabolic and signaling pathways have a close relationship with systemic oxidative stress and inflammation, both critically related to the development of obesity and the appearance of many linked comorbidities [ 6 , 20 ].…”

Exploring the impact of lipid droplets on the evolution and progress of hepatocarcinoma

“…Once TGs have been stored within LDs, these organelles are regulated by LD-associated proteins, known as perilipins (PLINs) ( Figure 1 ) ( Bombarda-Rocha et al, 2023 ). These proteins play a critical role in transitioning LDs from simple structures of inactive lipid storage to fully functional organelles that are integrally involved in lipid metabolism ( Bombarda-Rocha et al, 2023 ).…”

“…Once TGs have been stored within LDs, these organelles are regulated by LD-associated proteins, known as perilipins (PLINs) ( Figure 1 ) ( Bombarda-Rocha et al, 2023 ). These proteins play a critical role in transitioning LDs from simple structures of inactive lipid storage to fully functional organelles that are integrally involved in lipid metabolism ( Bombarda-Rocha et al, 2023 ). There are five distinct types of perilipins (PLIN1-5), each with specific expression patterns and metabolic activations, yet all are capable of regulating lipase activity on LDs ( Bombarda-Rocha et al, 2023 ).…”

“…These proteins play a critical role in transitioning LDs from simple structures of inactive lipid storage to fully functional organelles that are integrally involved in lipid metabolism ( Bombarda-Rocha et al, 2023 ). There are five distinct types of perilipins (PLIN1-5), each with specific expression patterns and metabolic activations, yet all are capable of regulating lipase activity on LDs ( Bombarda-Rocha et al, 2023 ). This diversity establishes a complex orchestrated mechanism that is directly linked to the healthy balance between lipogenesis and lipolysis ( Bombarda-Rocha et al, 2023 ).…”

“…There are five distinct types of perilipins (PLIN1-5), each with specific expression patterns and metabolic activations, yet all are capable of regulating lipase activity on LDs ( Bombarda-Rocha et al, 2023 ). This diversity establishes a complex orchestrated mechanism that is directly linked to the healthy balance between lipogenesis and lipolysis ( Bombarda-Rocha et al, 2023 ).…”