# PLIN5

## Overview
The PLIN5 gene encodes the protein perilipin 5, which is a member of the perilipin family of proteins associated with lipid droplets. Perilipin 5 plays a pivotal role in lipid metabolism, particularly in tissues with high rates of fatty acid oxidation such as skeletal muscle, heart, and liver. It is involved in the regulation of triglyceride storage and mobilization, facilitating the interaction between lipid droplets and mitochondria, thereby enhancing fatty acid oxidation (Granneman2011Interactions; Wang2011Perilipin). The protein is characterized by its ability to recruit mitochondria to lipid droplets, a function that distinguishes it from other perilipins (Wang2011Perilipin). This recruitment is crucial for directing fatty acids towards mitochondrial oxidation, especially under conditions of high energy demand (Mason2015Unraveling). The activity of perilipin 5 is regulated by phosphorylation and is influenced by metabolic regulators such as peroxisome proliferator-activated receptors (PPARs) (Pollak2015The; Mason2015Unraveling). Alterations in PLIN5 expression or function have been implicated in metabolic disorders, including non-alcoholic fatty liver disease and cardiac lipotoxicity (Kolleritsch2019Low; Mass2021Understanding).

## Structure
Perilipin 5 (PLIN5) is a protein associated with lipid droplets and plays a crucial role in lipid metabolism. The molecular structure of PLIN5 includes a C-terminal domain, known as the tether domain, which spans amino acids 425-463. This domain is essential for lipid droplet-mitochondria contacts and is composed of two α-helices with a hydrophobic pocket, potentially involved in lipid binding (Miner2022Perilipin). The tether domain interacts with the acyl-CoA synthetase Fatp4, facilitating fatty acid transport from lipid droplets to mitochondria for β-oxidation (Miner2022Perilipin).

PLIN5 also contains an N-terminal region that acts as a lipolytic barrier, promoting fatty acid storage, a feature conserved among perilipins (Miner2022Perilipin). The protein is phosphorylated at serine 155, a modification crucial for its role in fatty acid transport and regulation by protein kinase A (PKA) (Miner2022Perilipin; Pollak2015The).

PLIN5 shares high sequence similarity with other perilipins, such as PLIN2 and PLIN3, but uniquely recruits mitochondria to lipid droplets, a function not shared by PLIN3 under normal conditions (Wang2011Perilipin). The C-terminal 20 amino acids are particularly important for its function and are conserved among PLIN5 proteins (Wang2011Perilipin).

## Function
Perilipin 5 (PLIN5) is a lipid droplet-associated protein that plays a significant role in lipid metabolism, particularly in tissues with high fatty acid oxidation such as skeletal muscle, heart, and liver. PLIN5 is involved in the regulation of triglyceride storage and mobilization, facilitating the interaction between lipid droplets and mitochondria. It promotes both triglyceride storage and fatty acid oxidation by coordinating the colocalization and interaction of lipolytic enzymes like adipose triglyceride lipase (ATGL) and α-β-hydrolase domain-containing 5 (Abhd5) on the surface of lipid droplets (Granneman2011Interactions; Wang2011Perilipin).

PLIN5 is known to recruit mitochondria to the lipid droplet surface, enhancing the oxidative capacity of cells by directing fatty acids towards mitochondrial oxidation, especially under conditions of high energy demand (Wang2011Perilipin; Mason2015Unraveling). This protein also plays a role in stabilizing lipid droplets by inhibiting their hydrolysis, thus channeling fatty acids into triglyceride stores and reducing their oxidation by mitochondria (Wang2011Perilipin).

In healthy human cells, PLIN5 expression is associated with increased fatty acid oxidation and mitochondrial function, contributing to insulin sensitivity, particularly in exercise-trained individuals (GallardoMontejano2016Nuclear). Its activity is regulated by peroxisome proliferator-activated receptors (PPARs), which modulate its expression in response to metabolic demands (Mason2015Unraveling).

## Clinical Significance
Alterations in the expression or function of the PLIN5 gene have been implicated in several diseases, particularly those related to lipid metabolism. In non-alcoholic fatty liver disease (NAFLD), increased PLIN5 expression is associated with lipid droplet accumulation in the liver, contributing to a lipotoxic environment that can progress to hepatocellular carcinoma (HCC) (Mass2021Understanding). PLIN5 is also involved in managing oxidative stress and inflammation, processes that are crucial in the development of NAFLD and its progression to more severe liver conditions (Mass2021Understanding).

In the heart, PLIN5 mutations or altered expression can affect cardiac lipid metabolism and mitochondrial dynamics. The PLIN5-S155A mutation, for example, leads to triglyceride accumulation in cardiac muscle, which, despite not impairing heart function under mild stress, suggests a complex role in cardiac lipotoxicity (Kolleritsch2019Low). PLIN5 overexpression in cardiac tissue is linked to reduced mitochondrial fission, potentially protecting against lipotoxic heart dysfunction (Kolleritsch2019Low).

PLIN5's role in podocyte lipotoxicity has also been studied in the context of Alport syndrome, a genetic condition affecting kidney function, though specific findings on this relationship are limited (Kim2020Role).

## Interactions
PLIN5 (perilipin 5) is known to interact with several proteins involved in lipid metabolism, playing a crucial role in regulating lipolysis and fatty acid transport. It directly interacts with adipose triglyceride lipase (ATGL) on lipid droplets, facilitating the localization of ATGL to these droplets and promoting lipolysis (Wang2011Unique). This interaction is specific to PLIN5, as ATGL does not co-immunoprecipitate with other perilipins (Wang2011Unique).

PLIN5 also interacts with CGI-58, a co-activator of ATGL, in a mutually exclusive manner, suggesting a regulatory role in lipolytic stimulation (Gemmink2018Superresolution). The phosphorylation of PLIN5 by protein kinase A (PKA) is crucial for modulating its interactions, particularly with CGI-58, which is necessary for ATGL-mediated triglyceride breakdown (Pollak2015The).

In addition to its role in lipolysis, PLIN5 is involved in forming lipid droplet-mitochondria contact sites, interacting with Fatp4 to facilitate fatty acid transport to mitochondria for β-oxidation (Miner2022Perilipin). This interaction is essential for efficient fatty acid trafficking and is regulated by the phosphorylation of PLIN5 (Miner2022Perilipin).


## References


[1. (GallardoMontejano2016Nuclear) Violeta I. Gallardo-Montejano, Geetu Saxena, Christine M. Kusminski, Chaofeng Yang, John L. McAfee, Lisa Hahner, Kathleen Hoch, William Dubinsky, Vihang A. Narkar, and Perry E. Bickel. Nuclear perilipin 5 integrates lipid droplet lipolysis with pgc-1α/sirt1-dependent transcriptional regulation of mitochondrial function. Nature Communications, August 2016. URL: http://dx.doi.org/10.1038/ncomms12723, doi:10.1038/ncomms12723. This article has 109 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/ncomms12723)

[2. (Wang2011Perilipin) Hong Wang, Urmilla Sreenivasan, Hong Hu, Andrew Saladino, Brian M. Polster, Linda M. Lund, Da-wei Gong, William C. Stanley, and Carole Sztalryd. Perilipin 5, a lipid droplet-associated protein, provides physical and metabolic linkage to mitochondria. Journal of Lipid Research, 52(12):2159–2168, December 2011. URL: http://dx.doi.org/10.1194/jlr.m017939, doi:10.1194/jlr.m017939. This article has 365 citations and is from a peer-reviewed journal.](https://doi.org/10.1194/jlr.m017939)

[3. (Mason2015Unraveling) Rachael R. Mason and Matthew J. Watt. Unraveling the roles of plin5: linking cell biology to physiology. Trends in Endocrinology & Metabolism, 26(3):144–152, March 2015. URL: http://dx.doi.org/10.1016/j.tem.2015.01.005, doi:10.1016/j.tem.2015.01.005. This article has 64 citations.](https://doi.org/10.1016/j.tem.2015.01.005)

[4. (Mass2021Understanding) Paola Berenice Mass Sanchez, Marinela Krizanac, Ralf Weiskirchen, and Anastasia Asimakopoulos. Understanding the role of perilipin 5 in non-alcoholic fatty liver disease and its role in hepatocellular carcinoma: a review of novel insights. International Journal of Molecular Sciences, 22(10):5284, May 2021. URL: http://dx.doi.org/10.3390/ijms22105284, doi:10.3390/ijms22105284. This article has 16 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/ijms22105284)

[5. (Wang2011Unique) Hong Wang, Ming Bell, Urmilla Sreenevasan, Hong Hu, Jun Liu, Knut Dalen, Constantine Londos, Tomohiro Yamaguchi, Megan A. Rizzo, Rosalind Coleman, Dawei Gong, Dawn Brasaemle, and Carole Sztalryd. Unique regulation of adipose triglyceride lipase (atgl) by perilipin 5, a lipid droplet-associated protein. Journal of Biological Chemistry, 286(18):15707–15715, May 2011. URL: http://dx.doi.org/10.1074/jbc.m110.207779, doi:10.1074/jbc.m110.207779. This article has 200 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.m110.207779)

[6. (Gemmink2018Superresolution) Anne Gemmink, Sabine Daemen, Helma J.H. Kuijpers, Gert Schaart, Hans Duimel, Carmen López-Iglesias, Marc A.M.J. van Zandvoort, Kèvin Knoops, and Matthijs K.C. Hesselink. Super-resolution microscopy localizes perilipin 5 at lipid droplet-mitochondria interaction sites and at lipid droplets juxtaposing to perilipin 2. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 1863(11):1423–1432, November 2018. URL: http://dx.doi.org/10.1016/j.bbalip.2018.08.016, doi:10.1016/j.bbalip.2018.08.016. This article has 65 citations.](https://doi.org/10.1016/j.bbalip.2018.08.016)

[7. (Kolleritsch2019Low) Stephanie Kolleritsch, Benedikt Kien, Gabriele Schoiswohl, Clemens Diwoky, Renate Schreiber, Christoph Heier, Lisa Katharina Maresch, Martina Schweiger, Thomas O Eichmann, Sarah Stryeck, Petra Krenn, Tamara Tomin, Matthias Schittmayer, Dagmar Kolb, Thomas Rülicke, Gerald Hoefler, Heimo Wolinski, Tobias Madl, Ruth Birner-Gruenberger, and Guenter Haemmerle. Low cardiac lipolysis reduces mitochondrial fission and prevents lipotoxic heart dysfunction in perilipin 5 mutant mice. Cardiovascular Research, May 2019. URL: http://dx.doi.org/10.1093/cvr/cvz119, doi:10.1093/cvr/cvz119. This article has 40 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1093/cvr/cvz119)

[8. (Pollak2015The) Nina M. Pollak, Doris Jaeger, Stephanie Kolleritsch, Robert Zimmermann, Rudolf Zechner, Achim Lass, and Guenter Haemmerle. The interplay of protein kinase a and perilipin 5 regulates cardiac lipolysis*. Journal of Biological Chemistry, 290(3):1295–1306, January 2015. URL: http://dx.doi.org/10.1074/jbc.m114.604744, doi:10.1074/jbc.m114.604744. This article has 74 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.m114.604744)

[9. (Granneman2011Interactions) James G. Granneman, Hsiao-Ping H. Moore, Emilio P. Mottillo, Zhengxian Zhu, and Li Zhou. Interactions of perilipin-5 (plin5) with adipose triglyceride lipase. Journal of Biological Chemistry, 286(7):5126–5135, February 2011. URL: http://dx.doi.org/10.1074/jbc.M110.180711, doi:10.1074/jbc.m110.180711. This article has 246 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.M110.180711)

10. (Miner2022Perilipin) Perilipin 5 interacts with Fatp4 at membrane contact sites to promote lipid droplet-to-mitochondria fatty acid transport. This article has 5 citations.

[11. (Kim2020Role) Jin Ju Kim, Sydney S. Wilbon, Judith T. Molina David, Sandra M. Merscher, Flavia Fontanesi, Jeffrey H. Miner, and Alessia Fornoni. Role of plin5 deficiency in podocyte lipotoxicity and the progression of alport syndrome: po1723. Journal of the American Society of Nephrology, 31(10S):541–541, October 2020. URL: http://dx.doi.org/10.1681/asn.20203110s1541b, doi:10.1681/asn.20203110s1541b. This article has 0 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1681/asn.20203110s1541b)