Perilipin-2 Explained

Adipose differentiation-related protein, also known as perilipin 2, ADRP or adipophilin, is a protein which belongs to the perilipin (PAT) family of cytoplasmic lipid droplet (CLD)–binding proteins.^[1] In humans it is encoded by the ADFP gene.^[2] This protein surrounds the lipid droplet along with phospholipids and is involved in assisting the storage of neutral lipids within the lipid droplets.^[3]

Discovery

The adipose differentiation related protein (ADRP) was first characterized as an mRNA molecule that express early in adipocyte differentiation. The full length cDNA was cloned by rapid amplification of cDNA ends method and sequence analysis results in a protein with 425 amino acids that is unique and similar sequences had not previously been reported.^[4]

Gene location

In humans, the gene for adipose differentiation related protein is located at short p arm of chromosome 9 at region 22 band 1 from base pair 19108391 to 19127606 (GRCh38.p7) (map).^[5]

Protein structure

The proposed models for adipose differentiation related protein (perilipin 2) is maintained by the protein model portal.^[6] It is based on homology modelling and no models were found with greater than 90 percent homology. Perlipin 2 has three different functional domains . 1-115 amino acid sequences at N-terminal is highly similar with other perlipin family proteins and is required for stabilization of lipid droplets, 103-215 mid- region is needed for binding at lipid droplets while the C-terminal sequence from 220-437 forms four helix bundles.^[7]

Function

Perilipin 2 was thought to be expressed only in adipose tissues previously.^[8] However, later on it was found to be expressed in all types of cells including many non-adipose tissues.^[8] The function of perilipin 2 involves the formation of lipid droplets, formation of fatty liver by increasing uptake of fatty acids etc. Decreased expression of perilipin 2 decreases the fatty liver while increase expression of perilipin is associated with several metabolic diseases like type 2 diabetes, insulin resistance, heart diseases. Moreover, its expression was also found to be linked with other age related diseases. This protein is associated with the globule surface membrane material and is major constituent of the globule surface. Increase in mRNA levels is one of the earliest indications of adipocyte differentiation.^[2]

Pre-adipocytes are undifferentiated fibroblasts that can be stimulated to form adipocytes. Studies have shed light into potential molecular mechanisms in the fate determination of pre-adipocytes although the exact lineage of adipocyte is still unclear.^[9]

Mutation

In humans, a substitution mutation at the C-terminal region of perlipin 2 was shown to affect both the structure and function of the protein.^[7] At 251 position, serine residue was substituted by proline which results in the disruption of predicted alpha helical structure of the protein as well as reduction in the plasma triglycerides and lipolysis.^[10] Thus, mutation in perlipin 2 may influence the development of different human metabolic diseases.

In vitro and animal studies

Metabolic disorders and liver diseases

Conditions like obesity, type 2 diabetes are related with metabolic disorders. It involves increase accumulation of lipid due to impaired fatty acid metabolism. Alcoholic liver diseases and non-alcoholic fatty liver disease are two types of conditions associated with liver lipid accumulation.^[11] Obesity is related with increase accumulation of lipid droplets in non-adipose tissues causing lipotoxicity. The expression of perlipin 2 at normal level appears necessary to induce obesity in mouse model. Increased activity of perlipin 2 increases the resistance to insulin thereby promoting type 2 diabetes.^[11]

Cardiovascular diseases

Age related diseases like atherosclerosis, hypertension accounts many deaths in elderly people.^[12] Accumulation of lipid droplets induce the modification of macrophages to foam cells. Lysis of foam cells resulted in Atherosclerotic plaques and such plaques rupture and blocked the thrombotic vessel.^[12] Perlipin 2 protein around the macrophages and foam cells was found to play important role in formation of atheroma. Downregulation of perlipin 2 inhibits the lipid droplet accumulation and decreases the likelihood to convert macrophages to foam cells.^[13]

Cancer

Another factor which increases the risk for cancer is aging process.^[14] Analysis of body fluids like urine and blood from circulation from different types of cancer for example colorectal cancer, Burkitt cancer, lung adenocarcinoma showed increase level of Perlipin 2.^[15] Perlipin 2 can also serve as a biomarker for early detection of some type of cancer.^[16]

Further reading

• Bosma M, Hesselink MK, Sparks LM, Timmers S, Ferraz MJ, Mattijssen F, van Beurden D, Schaart G, de Baets MH, Verheyen FK, Kersten S, Schrauwen P . Perilipin 2 improves insulin sensitivity in skeletal muscle despite elevated intramuscular lipid levels . Diabetes . 61 . 11 . 2679–90 . November 2012 . 22807032 . 10.2337/db11-1402 . 3478528.
• Heid HW, Schnölzer M, Keenan TW . Adipocyte differentiation-related protein is secreted into milk as a constituent of milk lipid globule membrane . The Biochemical Journal . 320 . 3 . 1025–30 . December 1996 . 9003395 . 1218030 . 10.1042/bj3201025.
• Heid HW, Moll R, Schwetlick I, Rackwitz HR, Keenan TW . Adipophilin is a specific marker of lipid accumulation in diverse cell types and diseases . Cell and Tissue Research . 294 . 2 . 309–21 . November 1998 . 9799447 . 10.1007/s004410051181 . 9990761 .
• Schultz CJ, Torres E, Londos C, Torday JS . Role of adipocyte differentiation-related protein in surfactant phospholipid synthesis by type II cells . American Journal of Physiology. Lung Cellular and Molecular Physiology . 283 . 2 . L288–96 . August 2002 . 12114189 . 10.1152/ajplung.00204.2001 . 24026044 .
• Saarikoski ST, Rivera SP, Hankinson O . Mitogen-inducible gene 6 (MIG-6), adipophilin and tuftelin are inducible by hypoxia . FEBS Letters . 530 . 1–3 . 186–90 . October 2002 . 12387890 . 10.1016/S0014-5793(02)03475-0 . 37181106 .
• Targett-Adams P, Chambers D, Gledhill S, Hope RG, Coy JF, Girod A, McLauchlan J . Live cell analysis and targeting of the lipid droplet-binding adipocyte differentiation-related protein . The Journal of Biological Chemistry . 278 . 18 . 15998–6007 . May 2003 . 12591929 . 10.1074/jbc.M211289200 . free .
• Bildirici I, Roh CR, Schaiff WT, Lewkowski BM, Nelson DM, Sadovsky Y . The lipid droplet-associated protein adipophilin is expressed in human trophoblasts and is regulated by peroxisomal proliferator-activated receptor-gamma/retinoid X receptor . The Journal of Clinical Endocrinology and Metabolism . 88 . 12 . 6056–62 . December 2003 . 14671211 . 10.1210/jc.2003-030628 . free .
• Larigauderie G, Furman C, Jaye M, Lasselin C, Copin C, Fruchart JC, Castro G, Rouis M . Adipophilin enhances lipid accumulation and prevents lipid efflux from THP-1 macrophages: potential role in atherogenesis . Arteriosclerosis, Thrombosis, and Vascular Biology . 24 . 3 . 504–10 . March 2004 . 14707038 . 10.1161/01.ATV.0000115638.27381.97 . free .
• Nakamura N, Akashi T, Taneda T, Kogo H, Kikuchi A, Fujimoto T . ADRP is dissociated from lipid droplets by ARF1-dependent mechanism . Biochemical and Biophysical Research Communications . 322 . 3 . 957–65 . September 2004 . 15336557 . 10.1016/j.bbrc.2004.08.010 .
• Robenek H, Lorkowski S, Schnoor M, Troyer D . Spatial integration of TIP47 and adipophilin in macrophage lipid bodies . The Journal of Biological Chemistry . 280 . 7 . 5789–94 . February 2005 . 15545278 . 10.1074/jbc.M407194200 . free .
• Masuda Y, Itabe H, Odaki M, Hama K, Fujimoto Y, Mori M, Sasabe N, Aoki J, Arai H, Takano T . ADRP/adipophilin is degraded through the proteasome-dependent pathway during regression of lipid-storing cells . Journal of Lipid Research . 47 . 1 . 87–98 . January 2006 . 16230742 . 10.1194/jlr.M500170-JLR200 . free .
• Tobin KA, Harsem NK, Dalen KT, Staff AC, Nebb HI, Duttaroy AK . Regulation of ADRP expression by long-chain polyunsaturated fatty acids in BeWo cells, a human placental choriocarcinoma cell line . Journal of Lipid Research . 47 . 4 . 815–23 . April 2006 . 16391323 . 10.1194/jlr.M500527-JLR200 . free .
• Dalen KT, Ulven SM, Arntsen BM, Solaas K, Nebb HI . PPARalpha activators and fasting induce the expression of adipose differentiation-related protein in liver . Journal of Lipid Research . 47 . 5 . 931–43 . May 2006 . 16489205 . 10.1194/jlr.M500459-JLR200 . free .
• Ohsaki Y, Maeda T, Maeda M, Tauchi-Sato K, Fujimoto T . Recruitment of TIP47 to lipid droplets is controlled by the putative hydrophobic cleft . Biochemical and Biophysical Research Communications . 347 . 1 . 279–87 . August 2006 . 16808905 . 10.1016/j.bbrc.2006.06.074 .
• Magra AL, Mertz PS, Torday JS, Londos C . Role of adipose differentiation-related protein in lung surfactant production: a reassessment . Journal of Lipid Research . 47 . 11 . 2367–73 . November 2006 . 16936283 . 10.1194/jlr.M600157-JLR200 . free .
• Yao M, Huang Y, Shioi K, Hattori K, Murakami T, Nakaigawa N, Kishida T, Nagashima Y, Kubota Y . Expression of adipose differentiation-related protein: a predictor of cancer-specific survival in clear cell renal carcinoma . Clinical Cancer Research . 13 . 1 . 152–60 . January 2007 . 17200350 . 10.1158/1078-0432.CCR-06-1877 . free .
• Sarov-Blat L, Kiss RS, Haidar B, Kavaslar N, Jaye M, Bertiaux M, Steplewski K, Hurle MR, Sprecher D, McPherson R, Marcel YL . Predominance of a proinflammatory phenotype in monocyte-derived macrophages from subjects with low plasma HDL-cholesterol . Arteriosclerosis, Thrombosis, and Vascular Biology . 27 . 5 . 1115–22 . May 2007 . 17322100 . 10.1161/ATVBAHA.106.138990 . free .

Notes and References

1. Orlicky DJ, Degala G, Greenwood C, Bales ES, Russell TD, McManaman JL . Multiple functions encoded by the N-terminal PAT domain of adipophilin . Journal of Cell Science . 121 . Pt 17 . 2921–9 . September 2008 . 18697835 . 10.1242/jcs.026153 . 3139108.
2. Web site: Entrez Gene: ADFP adipose differentiation-related protein.
3. Conte M, Franceschi C, Sandri M, Salvioli S . Perilipin 2 and Age-Related Metabolic Diseases: A New Perspective . Trends in Endocrinology and Metabolism . September 2016 . 27659144 . 10.1016/j.tem.2016.09.001 . 27 . 12 . 893–903. 3651182 .
4. Jiang HP, Serrero G . Isolation and characterization of a full-length cDNA coding for an adipose differentiation-related protein . Proceedings of the National Academy of Sciences of the United States of America . 89 . 17 . 7856–60 . September 1992 . 1518805 . 49813 . 10.1073/pnas.89.17.7856 . 1992PNAS...89.7856J . free .
5. Web site: Homo sapiens (human) Annotation Release 107 (Current) . NCBI map viewer .
6. Web site: Q99541 . .
7. Magné J, Aminoff A, Perman Sundelin J, Mannila MN, Gustafsson P, Hultenby K, Wernerson A, Bauer G, Listenberger L, Neville MJ, Karpe F, Borén J, Ehrenborg E . 6. The minor allele of the missense polymorphism Ser251Pro in perilipin 2 (PLIN2) disrupts an α-helix, affects lipolysis, and is associated with reduced plasma triglyceride concentration in humans . FASEB J. . 27 . 8 . 3090–9 . August 2013 . 23603836 . 10.1096/fj.13-228759 . free. 205370787.
8. Brasaemle DL, Barber T, Wolins NE, Serrero G, Blanchette-Mackie EJ, Londos C . Adipose differentiation-related protein is an ubiquitously expressed lipid storage droplet-associated protein . Journal of Lipid Research . 38 . 11 . 2249–63 . November 1997 . 10.1016/S0022-2275(20)34939-7 . 9392423 . free .
9. Coskun H, Summerfield TL, Kniss DA, Friedman A . Mathematical modeling of preadipocyte fate determination . Journal of Theoretical Biology . 265 . 1 . 87–94 . July 2010 . 20385145 . 10.1016/j.jtbi.2010.03.047 . 2010JThBi.265...87C .
10. Sentinelli F, Capoccia D, Incani M, Bertoccini L, Severino A, Pani MG, Manconi E, Cossu E, Leonetti F, Baroni MG . The perilipin 2 (PLIN2) gene Ser251Pro missense mutation is associated with reduced insulin secretion and increased insulin sensitivity in Italian obese subjects . Diabetes Metab. Res. Rev. . 32 . 6 . 550–6 . September 2016 . 26443937 . 10.1002/dmrr.2751 . 5256380 .
11. Carr RM, Peralta G, Yin X, Ahima RS . Absence of perilipin 2 prevents hepatic steatosis, glucose intolerance and ceramide accumulation in alcohol-fed mice . PLOS ONE . 9 . 5 . e97118 . 2014 . 24831094 . 10.1371/journal.pone.0097118 . 4022498. 2014PLoSO...997118C . free .
12. Son SH, Goo YH, Choi M, Saha PK, Oka K, Chan LC, Paul A . Enhanced atheroprotection and lesion remodelling by targeting the foam cell and increasing plasma cholesterol acceptors . Cardiovascular Research . 109 . 2 . 294–304 . February 2016 . 26487692 . 10.1093/cvr/cvv241 . 4724936 .
13. Larigauderie G, Cuaz-Pérolin C, Younes AB, Furman C, Lasselin C, Copin C, Jaye M, Fruchart JC, Rouis M . Adipophilin increases triglyceride storage in human macrophages by stimulation of biosynthesis and inhibition of beta-oxidation . FEBS J. . 273 . 15 . 3498–510 . August 2006 . 16884492 . 10.1111/j.1742-4658.2006.05357.x . 27830334 . free .
14. Matsubara J, Honda K, Ono M, Sekine S, Tanaka Y, Kobayashi M, Jung G, Sakuma T, Nakamori S, Sata N, Nagai H, Ioka T, Okusaka T, Kosuge T, Tsuchida A, Shimahara M, Yasunami Y, Chiba T, Yamada T . Identification of adipophilin as a potential plasma biomarker for colorectal cancer using label-free quantitative mass spectrometry and protein microarray . Cancer Epidemiology, Biomarkers & Prevention . 20 . 10 . 2195–203 . October 2011 . 21828233 . 10.1158/1055-9965.EPI-11-0400 . free . 2433/197220 . free .
15. Zhang XD, Li W, Zhang N, Hou YL, Niu ZQ, Zhong YJ, Zhang YP, Yang SY . Identification of adipophilin as a potential diagnostic tumor marker for lung adenocarcinoma . International Journal of Clinical and Experimental Medicine . 7 . 4 . 1190–6 . 2014 . 24955208 . 4057887.
16. Prieto DA, Johann DJ, Wei BR, Ye X, Chan KC, Nissley DV, Simpson RM, Citrin DE, Mackall CL, Linehan WM, Blonder J . Mass spectrometry in cancer biomarker research: a case for immunodepletion of abundant blood-derived proteins from clinical tissue specimens . . 8 . 2 . 269–86 . 2014 . 24521024 . 10.2217/bmm.13.101 . 4201940.