# PLIN1

## Overview
PLIN1, or perilipin 1, is a gene that encodes a lipid droplet-associated protein primarily found in adipocytes, where it plays a pivotal role in lipid metabolism. The protein perilipin 1 is categorized as a lipid droplet-associated protein and is integral to the regulation of lipid storage and mobilization. It functions by controlling the access of lipases to lipid droplets, thereby modulating lipolysis and energy balance within cells. The PLIN1 gene produces several splice variants, which contribute to the protein's diverse functional roles in lipid droplet dynamics. Perilipin 1's activity is regulated through post-translational modifications, such as phosphorylation, which influence its interaction with other proteins involved in lipolysis. Mutations in the PLIN1 gene have been linked to metabolic disorders, including familial partial lipodystrophy and precocious acute coronary syndrome, highlighting its significance in maintaining lipid homeostasis and metabolic health (Kimmel2016The; Gandotra2011Perilipin; Hansen2017Visualization).

## Structure
PLIN1 (perilipin 1) is a protein associated with lipid droplets, primarily in adipocytes. Its primary structure consists of a sequence of amino acids encoded by the PLIN1 gene, with several splice variants, including Plin1a, 1b, 1c, and 1d, which differ at their C termini (Kimmel2016The). The secondary structure of PLIN1 includes a hydrophobic PAT domain and a repeating 11-mer helical motif, which are crucial for lipid droplet binding (Kimmel2016The). 

The tertiary structure involves the folding of these elements into a three-dimensional shape, facilitating its interaction with lipid droplets. PLIN1 forms micro domains on the lipid droplet surface, which serve as docking centers for hormone-sensitive lipase (HSL) during lipolysis (Hansen2017Visualization). 

Post-translational modifications, particularly phosphorylation, play a significant role in regulating PLIN1's function. In murine Plin1a, there are six PKA phosphorylation sites, which are essential for modulating lipolytic rates (Kimmel2016The). These modifications lead to a reorganization of the lipid droplet scaffold, enhancing lipolytic activity (Kimmel2016The). 

PLIN1's structure and modifications are integral to its role in lipid metabolism, influencing both storage and mobilization processes.

## Function
PLIN1 (perilipin 1) is a critical protein in lipid metabolism, primarily active on the surface of cytosolic lipid droplets (CLDs) in adipocytes. It functions as a gatekeeper for lipid storage and mobilization by controlling the access of lipases to these lipid droplets. Under basal conditions, PLIN1 is unphosphorylated and sequesters lipases such as adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) away from CLDs, thereby suppressing lipolysis (Kimmel2016The). Upon β-adrenergic stimulation, PLIN1 undergoes phosphorylation by protein kinase A (PKA), which facilitates the recruitment of lipases to the CLD surface, significantly increasing lipolytic activity (Hansen2017Visualization).

PLIN1 also plays a role in regulating the size and stability of lipid droplets. It interacts with proteins like Cide-C (Fsp27) to modulate the formation of large lipid droplets, balancing triacylglycerol storage and mobilization (Kimmel2016The). In addition, PLIN1 is involved in the formation of micro domains on lipid droplets, which serve as docking sites for HSL and are crucial for hormonally-regulated lipolysis (Hansen2017Visualization). These processes are essential for maintaining lipid homeostasis and energy balance in human cells.

## Clinical Significance
Mutations in the PLIN1 gene are associated with several metabolic disorders, most notably familial partial lipodystrophy (FPLD). This condition is characterized by abnormal fat distribution, insulin resistance, severe dyslipidemia, and hepatic steatosis. Specific frameshift mutations, such as p.Leu404AlafsX158 and p.Val398GlyfsX166, lead to smaller adipocytes and impaired triglyceride storage, resulting in increased basal lipolysis and a dominantly inherited phenotype due to perilipin haploinsufficiency (Gandotra2011Perilipin). Another frameshift mutation, 439fs, is linked to FPLD4 and results in smaller lipid droplets and higher basal lipolytic rates, contributing to severe insulin resistance and hypertriglyceridemia (Kozusko2014Clinical).

PLIN1 mutations have also been implicated in the pathogenesis of precocious acute coronary syndrome (ACS). Studies have found that certain PLIN1 variants are associated with an increased risk of early-onset ACS, suggesting a potential role in cardiovascular disease (BonelloPalot2020High). These mutations may contribute to altered lipid metabolism, which is a common feature in both lipodystrophy and cardiovascular conditions. The presence of PLIN1 mutations in these diseases underscores the gene's critical role in maintaining normal lipid homeostasis and its potential impact on metabolic health.

## Interactions
PLIN1 (perilipin 1) is involved in several critical interactions with other proteins that regulate lipolysis. It interacts with hormone-sensitive lipase (HSL), facilitating its translocation to lipid droplets, which is essential for effective lipolysis. This interaction is mediated by specific regions within PLIN1, including the N-terminal region (amino acids 141-200) and the C-terminal region (amino acids 406-480) (Shen2009Functional). 

PLIN1 also interacts with CGI-58, a co-activator of adipose triglyceride lipase (ATGL). This interaction is crucial for regulating basal lipolysis, as mutations in PLIN1 that affect its ability to sequester CGI-58 lead to increased lipolytic activity and metabolic disorders (Kimmel2016The). 

Additionally, PLIN1 forms a scaffold around lipid droplets, organizing lipolytic proteins and creating distinct micro domains. Under lipolytic conditions, these domains are disrupted, indicating a dynamic interaction with the lipid droplet surface (Hansen2017Visualization). 

PLIN1's interactions are modulated by phosphorylation, which affects its role in lipid metabolism and the accessibility of lipases to triglycerides (Lin2014Membrane; Granneman2007Analysis).


## References


[1. (BonelloPalot2020High) Nathalie Bonello-Palot, Marc Laine, Thomas Cuisset, Thibault Ronchard, Camille Desgrouas, Françoise Merono, Manal Ibrahim-Kosta, Mathieu Cerino, Arnaud Blanchard, Patrice Bourgeois, Nicolas Levy, Anderson Loundou, Pierre-Emmanuel Morange, Marie-Christine Alessi, Catherine Badens, and Laurent Bonello. High prevalence of mutations in perilipin 1 in patients with precocious acute coronary syndrome. Atherosclerosis, 293:86–91, January 2020. URL: http://dx.doi.org/10.1016/j.atherosclerosis.2019.12.002, doi:10.1016/j.atherosclerosis.2019.12.002. This article has 2 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1016/j.atherosclerosis.2019.12.002)

[2. (Shen2009Functional) Wen-Jun Shen, Shailja Patel, Hideaki Miyoshi, Andrew S. Greenberg, and Fredric B. Kraemer. Functional interaction of hormone-sensitive lipase and perilipin in lipolysis. Journal of Lipid Research, 50(11):2306–2313, November 2009. URL: http://dx.doi.org/10.1194/jlr.m900176-jlr200, doi:10.1194/jlr.m900176-jlr200. This article has 98 citations and is from a peer-reviewed journal.](https://doi.org/10.1194/jlr.m900176-jlr200)

[3. (Lin2014Membrane) Penghui Lin, Xiao Chen, Hem Moktan, Estela L. Arrese, Lian Duan, Liying Wang, Jose L. Soulages, and Donghua H. Zhou. Membrane attachment and structure models of lipid storage droplet protein 1. Biochimica et Biophysica Acta (BBA) - Biomembranes, 1838(3):874–881, March 2014. URL: http://dx.doi.org/10.1016/j.bbamem.2013.12.003, doi:10.1016/j.bbamem.2013.12.003. This article has 16 citations.](https://doi.org/10.1016/j.bbamem.2013.12.003)

[4. (Gandotra2011Perilipin) Sheetal Gandotra, Caroline Le Dour, William Bottomley, Pascale Cervera, Philippe Giral, Yves Reznik, Guillaume Charpentier, Martine Auclair, Marc Delépine, Inês Barroso, Robert K. Semple, Mark Lathrop, Olivier Lascols, Jacqueline Capeau, Stephen O’Rahilly, Jocelyne Magré, David B. Savage, and Corinne Vigouroux. Perilipin deficiency and autosomal dominant partial lipodystrophy. New England Journal of Medicine, 364(8):740–748, February 2011. URL: http://dx.doi.org/10.1056/nejmoa1007487, doi:10.1056/nejmoa1007487. This article has 241 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1056/nejmoa1007487)

[5. (Hansen2017Visualization) Jesper S. Hansen, Sofia de Maré, Helena A. Jones, Olga Göransson, and Karin Lindkvist-Petersson. Visualization of lipid directed dynamics of perilipin 1 in human primary adipocytes. Scientific Reports, November 2017. URL: http://dx.doi.org/10.1038/s41598-017-15059-4, doi:10.1038/s41598-017-15059-4. This article has 41 citations and is from a peer-reviewed journal.](https://doi.org/10.1038/s41598-017-15059-4)

[6. (Kozusko2014Clinical) Kristina Kozusko, Venessa H.M. Tsang, William Bottomley, Yoon-Hi Cho, Sheetal Gandotra, Michael Mimmack, Koini Lim, Iona Isaac, Satish Patel, Vladimir Saudek, Stephen O’Rahilly, Shubha Srinivasan, Jerry R. Greenfield, Ines Barroso, Lesley V. Campbell, and David B. Savage. Clinical and molecular characterization of a novel plin1 frameshift mutation identified in patients with familial partial lipodystrophy. Diabetes, 64(1):299–310, August 2014. URL: http://dx.doi.org/10.2337/db14-0104, doi:10.2337/db14-0104. This article has 61 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.2337/db14-0104)

[7. (Kimmel2016The) Alan R. Kimmel and Carole Sztalryd. The perilipins: major cytosolic lipid droplet–associated proteins and their roles in cellular lipid storage, mobilization, and systemic homeostasis. Annual Review of Nutrition, 36(1):471–509, July 2016. URL: http://dx.doi.org/10.1146/annurev-nutr-071813-105410, doi:10.1146/annurev-nutr-071813-105410. This article has 256 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1146/annurev-nutr-071813-105410)

[8. (Granneman2007Analysis) James G. Granneman, Hsiao-Ping H. Moore, Rachel L. Granneman, Andrew S. Greenberg, Martin S. Obin, and Zhengxian Zhu. Analysis of lipolytic protein trafficking and interactions in adipocytes. Journal of Biological Chemistry, 282(8):5726–5735, February 2007. URL: http://dx.doi.org/10.1074/jbc.m610580200, doi:10.1074/jbc.m610580200. This article has 247 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.m610580200)