# PLIN2

## Overview
The PLIN2 gene encodes the protein perilipin 2, a member of the perilipin family, which plays a pivotal role in lipid metabolism. Perilipin 2 is a lipid droplet-associated protein that is ubiquitously expressed across various tissues and is integral to the regulation of lipid storage and mobilization. It is characterized by a complex structure that includes distinct domains essential for its function in lipid droplet targeting and stabilization (Najt2014Structural). As a constitutive lipid droplet protein, perilipin 2 is involved in maintaining lipid homeostasis by modulating the formation, stability, and degradation of lipid droplets, thereby influencing cellular lipid content and metabolic processes (Tsai2017The). The protein's interactions with other proteins and lipids further underscore its role in lipid droplet dynamics and lipid metabolism (McIntosh2012Direct). Alterations in the PLIN2 gene have been linked to various metabolic disorders, highlighting its clinical significance in conditions such as non-alcoholic fatty liver disease and obesity (McManaman2013Perilipin2null).

## Structure
The PLIN2 protein, also known as perilipin 2, is characterized by a complex molecular structure that includes distinct domains and secondary structural elements. The protein is primarily composed of α-helices and β-strands, with nine α-helices and five β-strands interconnected by random coils (Najt2014Structural). The N-terminal region of PLIN2 contains two β-strands and four α-helices, while the C-terminal region features an α-β domain and a 4-helix bundle, forming a deep cleft crucial for lipid binding (Najt2014Structural). This cleft is conserved within the perilipin family and is essential for the protein's function in lipid droplet targeting and stabilization (Najt2014Structural).

PLIN2's tertiary structure includes an apolipophorin III-like N-terminal domain and a TIP47-like C-terminal domain, linked by a helical linker (Najt2014Structural). The C-terminal domain's cleft interacts favorably with lipids such as stearic acid and cholesterol, with cholesterol showing a higher binding affinity (Najt2014Structural). The protein's structure is sensitive to ligand binding, which can affect its secondary structure, as seen with cholesterol increasing α-helical content (Najt2014Structural).

PLIN2 is expressed in various isoforms due to alternative splicing, and its function can be influenced by post-translational modifications like phosphorylation. These structural features and modifications are critical for PLIN2's role in lipid droplet formation and regulation.

## Function
PLIN2, or perilipin 2, is a constitutive lipid droplet protein that plays a significant role in lipid metabolism by regulating the formation, stability, and degradation of lipid droplets in cells. It is ubiquitously expressed and acts as a stabilizer for lipid droplets, preventing their degradation and limiting their accessibility for autophagosome biogenesis, thereby suppressing autophagy (Tsai2017The). In the liver, PLIN2 is involved in maintaining triglyceride homeostasis by modulating autophagy, which is crucial for lipid catabolism (Tsai2017The). 

In cardiomyocytes, PLIN2 is important for regulating lipid storage and mobilization. Its deficiency leads to increased triglyceride accumulation due to altered lipophagy, indicating its role in the proper hydrolysis of lipid droplets (Mardani2019Plin2deficiency). In the context of nonalcoholic fatty liver disease, PLIN2 expression is upregulated as a marker for steatosis, although its direct involvement in lipid storage during early stages of the disease is not evident (Graffmann2016Modeling). 

PLIN2 also influences cholesterol balance in the adrenal cortex by regulating cholesteryl ester-rich lipid droplets, although its absence does not significantly affect steroidogenesis (Li2021Plin2). Overall, PLIN2 is crucial for balancing lipid storage and breakdown, impacting cellular lipid content and metabolic processes.

## Clinical Significance
Mutations and alterations in the PLIN2 gene are associated with several metabolic disorders. The Ser251Pro missense mutation in PLIN2 has been linked to reduced insulin secretion and increased insulin sensitivity in obese individuals, suggesting its role in insulin dynamics independent of diabetes-related changes (Sentinelli2015The). This mutation is also associated with decreased plasma triglyceride and very low-density lipoprotein concentrations, although these effects were not consistently observed across different studies (Magne2013The).

PLIN2 expression levels are implicated in the development of non-alcoholic fatty liver disease (NAFLD) and obesity. PLIN2-null mice are protected against diet-induced obesity and fatty liver disease, indicating that PLIN2 contributes to lipid accumulation and metabolic dysregulation (McManaman2013Perilipin2null). In humans, high PLIN2 expression is linked to conditions such as sarcopenia, hepatic steatosis, and atherosclerosis, potentially due to its role in lipid droplet metabolism and storage (Conte2016Perilipin).

The Ser251Pro variant has also been associated with nonalcoholic steatohepatitis (NASH), a liver disease characterized by altered lipid droplet metabolism, suggesting a genetic risk factor for this condition (Faulkner2020A). These findings highlight the clinical significance of PLIN2 in metabolic diseases.

## Interactions
Perilipin 2 (PLIN2) is involved in various interactions with proteins that play significant roles in lipid droplet dynamics and lipid metabolism. PLIN2 interacts with the hepatitis C virus (HCV) core and NS5A proteins, facilitating their localization to lipid droplets, which is crucial for the production of infectious HCV particles (Lassen2018Perilipin2). It also interacts with Rab18, a protein associated with lipid droplets, enhancing Rab18's translocation from the endoplasmic reticulum to lipid droplets. This interaction is essential for Rab18's function in lipid droplet growth and morphology (Deng2020Rab18).

PLIN2 is involved in the AMPK-dependent phosphorylation process, which triggers its degradation via chaperone-mediated autophagy (CMA). This process is crucial for lipolysis, as it facilitates the removal of PLIN2 from lipid droplets (Kaushik2016AMPKdependent). Additionally, PLIN2 interacts with lipids on the surface of lipid droplets, directly associating with various lipids such as phosphatidylcholine, sphingomyelin, stearic acid, and cholesterol. These interactions suggest PLIN2's role in maintaining lipid droplet structure and function (McIntosh2012Direct).


## References


[1. (Najt2014Structural) Charles P. Najt, Joel S. Lwande, Avery L. McIntosh, Subramanian Senthivinayagam, Shipra Gupta, Leslie A. Kuhn, and Barbara P. Atshaves. Structural and functional assessment of perilipin 2 lipid binding domain(s). Biochemistry, 53(45):7051–7066, November 2014. URL: http://dx.doi.org/10.1021/bi500918m, doi:10.1021/bi500918m. This article has 40 citations and is from a peer-reviewed journal.](https://doi.org/10.1021/bi500918m)

[2. (McIntosh2012Direct) Avery L. McIntosh, Subramanian Senthivinayagam, Kenneth C. Moon, Shipra Gupta, Joel S. Lwande, Cameron C. Murphy, Stephen M. Storey, and Barbara P. Atshaves. Direct interaction of plin2 with lipids on the surface of lipid droplets: a live cell fret analysis. American Journal of Physiology-Cell Physiology, 303(7):C728–C742, October 2012. URL: http://dx.doi.org/10.1152/ajpcell.00448.2011, doi:10.1152/ajpcell.00448.2011. This article has 60 citations.](https://doi.org/10.1152/ajpcell.00448.2011)

[3. (Mardani2019Plin2deficiency) Ismena Mardani, Knut Tomas Dalen, Christina Drevinge, Azra Miljanovic, Marcus Ståhlman, Martina Klevstig, Margareta Scharin Täng, Per Fogelstrand, Max Levin, Matias Ekstrand, Syam Nair, Björn Redfors, Elmir Omerovic, Linda Andersson, Alan R. Kimmel, Jan Borén, and Malin C. Levin. Plin2-deficiency reduces lipophagy and results in increased lipid accumulation in the heart. Scientific Reports, May 2019. URL: http://dx.doi.org/10.1038/s41598-019-43335-y, doi:10.1038/s41598-019-43335-y. This article has 35 citations and is from a peer-reviewed journal.](https://doi.org/10.1038/s41598-019-43335-y)

[4. (Faulkner2020A) Claire S. Faulkner, Collin M. White, Vijay H. Shah, and Loretta L. Jophlin. A single nucleotide polymorphism of plin2 is associated with nonalcoholic steatohepatitis and causes phenotypic changes in hepatocyte lipid droplets: a pilot study. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 1865(5):158637, May 2020. URL: http://dx.doi.org/10.1016/j.bbalip.2020.158637, doi:10.1016/j.bbalip.2020.158637. This article has 11 citations.](https://doi.org/10.1016/j.bbalip.2020.158637)

5. (Deng2020Rab18) Rab18 Binds PLIN2 and ACSL3 to Mediate Lipid Droplet Dynamics. This article has 0 citations.

[6. (Kaushik2016AMPKdependent) Susmita Kaushik and Ana Maria Cuervo. Ampk-dependent phosphorylation of lipid droplet protein plin2 triggers its degradation by cma. Autophagy, 12(2):432–438, February 2016. URL: http://dx.doi.org/10.1080/15548627.2015.1124226, doi:10.1080/15548627.2015.1124226. This article has 173 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1080/15548627.2015.1124226)

[7. (Sentinelli2015The) Federica Sentinelli, Danila Capoccia, Michela Incani, Laura Bertoccini, Anna Severino, Maria Grazia Pani, Ettore Manconi, Efisio Cossu, Frida Leonetti, and Marco G. Baroni. The perilipin 2 (plin2) gene ser251pro missense mutation is associated with reduced insulin secretion and increased insulin sensitivity in italian obese subjects. Diabetes/Metabolism Research and Reviews, 32(6):550–556, November 2015. URL: http://dx.doi.org/10.1002/dmrr.2751, doi:10.1002/dmrr.2751. This article has 18 citations and is from a peer-reviewed journal.](https://doi.org/10.1002/dmrr.2751)

[8. (Graffmann2016Modeling) Nina Graffmann, Sarah Ring, Marie-Ann Kawala, Wasco Wruck, Audrey Ncube, Hans-Ingo Trompeter, and James Adjaye. Modeling nonalcoholic fatty liver disease with human pluripotent stem cell-derived immature hepatocyte-like cells reveals activation of plin2 and confirms regulatory functions of peroxisome proliferator-activated receptor alpha. Stem Cells and Development, 25(15):1119–1133, August 2016. URL: http://dx.doi.org/10.1089/scd.2015.0383, doi:10.1089/scd.2015.0383. This article has 83 citations and is from a peer-reviewed journal.](https://doi.org/10.1089/scd.2015.0383)

[9. (Li2021Plin2) Yuchuan Li, Prabhat Khanal, Frode Norheim, Marit Hjorth, Thomas Bjellaas, Christian A. Drevon, Jarle Vaage, Alan R. Kimmel, and Knut Tomas Dalen. Plin2 deletion increases cholesteryl ester lipid droplet content and disturbs cholesterol balance in adrenal cortex. Journal of Lipid Research, 62:100048, 2021. URL: http://dx.doi.org/10.1016/j.jlr.2021.100048, doi:10.1016/j.jlr.2021.100048. This article has 22 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.jlr.2021.100048)

[10. (Tsai2017The) Tsung-Huang Tsai, Elaine Chen, Lan Li, Pradip Saha, Hsiao-Ju Lee, Li-Shin Huang, Gregory S. Shelness, Lawrence Chan, and Benny Hung-Junn Chang. The constitutive lipid droplet protein plin2 regulates autophagy in liver. Autophagy, 13(7):1130–1144, June 2017. URL: http://dx.doi.org/10.1080/15548627.2017.1319544, doi:10.1080/15548627.2017.1319544. This article has 166 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1080/15548627.2017.1319544)

[11. (Conte2016Perilipin) Maria Conte, Claudio Franceschi, Marco Sandri, and Stefano Salvioli. Perilipin 2 and age-related metabolic diseases: a new perspective. Trends in Endocrinology & Metabolism, 27(12):893–903, December 2016. URL: http://dx.doi.org/10.1016/j.tem.2016.09.001, doi:10.1016/j.tem.2016.09.001. This article has 93 citations.](https://doi.org/10.1016/j.tem.2016.09.001)

[12. (Lassen2018Perilipin2) Susan Lassen, Cordula Grüttner, Van Nguyen-Dinh, and Eva Herker. Perilipin-2 is critical for efficient lipoprotein and hepatitis c virus particle production. Journal of Cell Science, January 2018. URL: http://dx.doi.org/10.1242/jcs.217042, doi:10.1242/jcs.217042. This article has 11 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1242/jcs.217042)

[13. (McManaman2013Perilipin2null) James L. McManaman, Elise S. Bales, David J. Orlicky, Matthew Jackman, Paul S. MacLean, Shannon Cain, Amanda E. Crunk, Ayla Mansur, Christine E. Graham, Thomas A. Bowman, and Andrew S. Greenberg. Perilipin-2-null mice are protected against diet-induced obesity, adipose inflammation, and fatty liver disease. Journal of Lipid Research, 54(5):1346–1359, May 2013. URL: http://dx.doi.org/10.1194/jlr.m035063, doi:10.1194/jlr.m035063. This article has 172 citations and is from a peer-reviewed journal.](https://doi.org/10.1194/jlr.m035063)