Perilipin-1 Explained

Perilipin, also known as lipid droplet-associated protein, perilipin 1, or PLIN, is a protein that, in humans, is encoded by the PLIN gene.[1] The perilipins are a family of proteins that associate with the surface of lipid droplets. Phosphorylation of perilipin is essential for the mobilization of fats in adipose tissue.[2]

Perilipin family of proteins

Perilipin is part of a gene family with six currently-known members. In vertebrates, closely related genes include adipophilin (also known as adipose differentiation-related protein or Perilipin 2), TIP47 (Perilipin 3), Perilipin 4 and Perilipin 5 (also called MLDP, LSDP5, or OXPAT). Insects express related proteins, LSD1 and LSD2, in fat bodies. The yeast Saccharomyces cerevisiae expresses PLN1 (formerly PET10), that stabilizes lipid droplets and aids in their assembly.[3]

Evolution

The perilipins are considered to have their origins in a common ancestral gene which, during the first and second vertebrate genome duplication,  gave rise to six types of PLIN genes.

Composition and structure

Human perilipin

Human perilipin-1 is composed by 522 amino acids, which add up to a molecular mass of 55.990 kDa. It presents an estimated number of 15 phosphorylation sites (residues 81, 85, 126, 130, 132, 137, 174, 299, 301, 382, 384, 408, 436, 497, 499 and 522)[4] from which 3 -those in bold- have been suggested to be relevant for stimulated-lipolysis through PKA phosphorylation - they correspond respectively to PKA Phosphorylation sites 1, 5 and 6.[5] A compositional bias of Glutamic acid can be found between residues 307 and 316.[6] Its secondary structure has been suggested to be conformed exclusively by partially hydrophobic α-helixes,[7] as well as the respective coils and bends.

Whereas perilipin-1 is coded by a single gene, alternative mRNA splicing processes can lead to three protein isoforms (Perilipin A, B and C). Both Perilipin A and B present common N-terminal regions, differing in the C-terminal ones.[8] Concretely, beginning from the N-terminal of Perilipin-1, a PAT domain—characteristic of its protein family—can be found, followed by an also characteristic repeated sequence of 13 residues which form amphipathic helixes with an active role in linking membranes[9] and a 4-helix bundle before the C-terminal carbon.[10] In Perilipin A, lipophile nature is conferred by the slightly hydrophobic amino acids concentrated in the central 25% of the sequence, region that anchors the protein to the core of the lipid droplet.[11]

Murine perilipin

Unlike its human ortholog, murine perilipin is composed of 517 amino acids in the primary structure of which several regions can be identified. Three moderately hydrophobic sequences (H1, H2, H3) of 18 rem (243-260 aa), 23 rem (320-332 aa) and 16 rem (349-364 aa) can be identified in the centre of the protein, as well as an acidic region of 28 residues where both glutamic and aspartic acids add up to 19 of them. Five sequences 18 residues long that could form amphipathic β-pleated sheets—according to a prediction made through LOCATE program—are found between aa 111 and 182. Serines occupying positions 81, 222, 276, 433, 492 and 517 act as phosphorylation sites -numbered from 1 to 6- for PKA,[12] as well as several other threonines and serines which add up to 27 phosphorylation sites.[13]

Function

Perilipin is a protein that coats lipid droplets (LDs) in adipocytes,[14] the fat-storing cells in adipose tissue. In fact, PLIN1 is greatly expressed in white adipocytes.[15]

It controls adipocyte lipid metabolism.[16] It handles essential functions in the regulation of basal and hormonally stimulated lipolysis[17] and also rises the formation of large LDs which implies an increase in the synthesis of triglycerides.

In humans, Perilipin A is the most abundant protein associated with the adipocyte LDs[18] and lower PLIN1 expression is related with higher rates of lipolysis.[19]

Under basal conditions, Perilipin acts as a protective coating of LDs from the body's natural lipases, such as hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL),[20] which break triglycerides into glycerol and free fatty acids for use in lipid metabolism.

In times of energy deficit, Perilipin is hyperphosphorylated by PKA following β-adrenergic receptor activation. Phosphorylated perilipin changes conformation, exposing the stored lipids to hormone-sensitive lipase-mediated lipolysis.

Modulator of adipocyte lipid metabolism

Specifically, in the basal state Perilipin A allows a low level of basal lipolysis[21] by reducing the access of cytosolic lipases to stored triacylglycerol in LDs. It is found at their surface in a complex with CGI-58, the co-activator of ATGL. ATGL might also be in this complex but it is quiescent.[22]

Under lipolytically stimulated conditions, PKA is activated and phosphorylates up to 6 Serine residues on Perilipin A (Ser81, 222, 276, 433, 492, and 517) and 2 on HSL (Ser659, and 660). Although PKA also phosphorylates HSL, which can increase its activity, the more than 50-fold increase in fat mobilization (triggered by epinephrine) is primarily due to Perilipin phosphorylation.

Then, Phosphorylated HSL translocates to the LD surface and associates with Perilipin A and Adipocyte fatty acid-binding protein (AFABP). Consequently, HSL gains access to triacylglycerol (TAG) and diacylglycerol (DAG), substrates in LDs. Also, CGI-58 separates from the LD outer layer which leads to a redistribution of ATGL. In particular, ATGL interacts with Perilipin A through phosphorylated Ser517.

As a result, PKA phosphorylation implies an enriched colocation of HLS and ATGL which facilitates maximal lipolysis by the two lipases.

Clinical significance

Perilipin is an important regulator of lipid storage. Both an overexpression or deficiency of the protein, caused by a mutation, lead to severe health issues.

Overexpression

Perilipin expression is elevated in obese animals and humans. Polymorphisms in the human perilipin (PLIN) gene have been associated with variance in body-weight regulation and may be a genetic influence on obesity risk in humans.[23]

This protein can be modified by O-linked acetylglucosamine (O-GlNac) moieties and the enzyme that intervenes is O-GlcNAc transferase (OGT). An abundance of OGT obstructs lipolysis and benefits diet-induced obesity and whole-body insulin resistance. Studies also propose that an overexpression of adipose O-GlcNAc signaling is a molecular expression of obesity and diabetes in humans.[24]

Deficiency

Perilipin-null mice eat more food than wild-type mice, but gain 1/3 less fat than wild-type mice on the same diet; perilipin-null mice are thinner, with more lean muscle mass.[25] Perilipin-null mice also exhibit enhanced leptin production and a greater tendency to develop insulin resistance than wild-type mice. Even though perilipin-null mice present less fat mass and a higher insulin resistance, they do not show signs of a whole lipodystrophic phenotype.[26]

In humans, studies suggest that a deficiency of PLIN1 causes lipodystrophic syndromes,[27] which disables the optimal accumulation of triglycerides in adipocytes that derives in an abnormal deposition of lipids in tissues such as skeletal muscle and liver. The storage of lipids in the liver leads to insulin resistance and hypertriglyceridemia. Affected patients are characterized by a subcutaneous fat with smaller than normal adipocytes, macrophage infiltration and fibrosis.

These findings affirm a new primary form of inherited lipodystrophy and emphasize on the severe metabolic consequences of a defect in the formation of lipid droplets in adipose tissue.

In particular, variants 13041A>G and 14995A>T have been associated with increased risk of obesity in women and 11482G>A has been associated with decreased perilipin expression and increased lipolysis in women.[28] [29]

Further reading

Notes and References

  1. Web site: Entrez Gene: PLIN perilipin.
  2. http://pharmaxchange.info/press/2013/10/mobilization-and-cellular-uptake-of-stored-fats-triacylglycerols-with-animation/ Mobilization and Cellular Uptake of Stored Fats (with Animation)
  3. Gao Q, Binns DD, Kinch LN, Grishin NV, Ortiz N, Chen X, Goodman JM . Pet10p is a yeast perilipin that stabilizes lipid droplets and promotes their assembly . The Journal of Cell Biology . 216 . 10 . 3199–3217 . October 2017 . 28801319 . 5626530 . 10.1083/jcb.201610013 .
  4. Bian Y, Song C, Cheng K, Dong M, Wang F, Huang J, Sun D, Wang L, Ye M, Zou H . 6 . An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome . Journal of Proteomics . 96 . 253–62 . January 2014 . 24275569 . 10.1016/j.jprot.2013.11.014 .
  5. Sztalryd C, Xu G, Dorward H, Tansey JT, Contreras JA, Kimmel AR, Londos C . Perilipin A is essential for the translocation of hormone-sensitive lipase during lipolytic activation . The Journal of Cell Biology . 161 . 6 . 1093–103 . June 2003 . 12810697 . 2172984 . 10.1083/jcb.200210169 .
  6. Web site: PLIN1 - Perilipin-1 - Homo sapiens (Human) - PLIN1 gene & protein. 2020-11-01. www.uniprot.org. en.
  7. Noureldein MH . In silico discovery of a perilipin 1 inhibitor to be used as a new treatment for obesity . European Review for Medical and Pharmacological Sciences . 18 . 4 . 457–60 . 2014 . 24610610 .
  8. Londos C, Brasaemle DL, Schultz CJ, Segrest JP, Kimmel AR . Perilipins, ADRP, and other proteins that associate with intracellular neutral lipid droplets in animal cells . Seminars in Cell & Developmental Biology . 10 . 1 . 51–8 . February 1999 . 10355028 . 10.1006/scdb.1998.0275 .
  9. Rowe ER, Mimmack ML, Barbosa AD, Haider A, Isaac I, Ouberai MM, Thiam AR, Patel S, Saudek V, Siniossoglou S, Savage DB . 6 . Conserved Amphipathic Helices Mediate Lipid Droplet Targeting of Perilipins 1-3 . The Journal of Biological Chemistry . 291 . 13 . 6664–78 . March 2016 . 26742848 . 4807253 . 10.1074/jbc.M115.691048 . free .
  10. Itabe H, Yamaguchi T, Nimura S, Sasabe N . Perilipins: a diversity of intracellular lipid droplet proteins . Lipids in Health and Disease . 16 . 1 . 83 . April 2017 . 28454542 . 5410086 . 10.1186/s12944-017-0473-y . free .
  11. Garcia A, Sekowski A, Subramanian V, Brasaemle DL . The central domain is required to target and anchor perilipin A to lipid droplets . The Journal of Biological Chemistry . 278 . 1 . 625–35 . January 2003 . 12407111 . 10.1074/jbc.M206602200 . 12795601 . free .
  12. Zhang HH, Souza SC, Muliro KV, Kraemer FB, Obin MS, Greenberg AS . Lipase-selective functional domains of perilipin A differentially regulate constitutive and protein kinase A-stimulated lipolysis . The Journal of Biological Chemistry . 278 . 51 . 51535–42 . December 2003 . 14527948 . 10.1074/jbc.M309591200 . 8227051 . free .
  13. Rogne M, Chu DT, Küntziger TM, Mylonakou MN, Collas P, Tasken K . OPA1-anchored PKA phosphorylates perilipin 1 on S522 and S497 in adipocytes differentiated from human adipose stem cells . Molecular Biology of the Cell . 29 . 12 . 1487–1501 . June 2018 . 29688805 . 6014102 . 10.1091/mbc.E17-09-0538 . Parton RG .
  14. Greenberg AS, Egan JJ, Wek SA, Garty NB, Blanchette-Mackie EJ, Londos C . Perilipin, a major hormonally regulated adipocyte-specific phosphoprotein associated with the periphery of lipid storage droplets . The Journal of Biological Chemistry . 266 . 17 . 11341–6 . June 1991 . 10.1016/S0021-9258(18)99168-4 . 2040638 . free .
  15. Shijun L, Khan R, Raza SH, Jieyun H, Chugang M, Kaster N, Gong C, Chunping Z, Schreurs NM, Linsen Z . 6 . Function and characterization of the promoter region of perilipin 1 (PLIN1): Roles of E2F1, PLAG1, C/EBPβ, and SMAD3 in bovine adipocytes . Genomics . 112 . 3 . 2400–2409 . May 2020 . 10.1016/j.ygeno.2020.01.012 . 31981700 . 210912743 . free .
  16. Web site: UniProtKB - O60240 (PLIN1_HUMAN).
  17. Brasaemle DL . Thematic review series: adipocyte biology. The perilipin family of structural lipid droplet proteins: stabilization of lipid droplets and control of lipolysis . Journal of Lipid Research . 48 . 12 . 2547–59 . December 2007 . 17878492 . 10.1194/jlr.R700014-JLR200 . 38744670 . free .
  18. Brasaemle DL, Subramanian V, Garcia A, Marcinkiewicz A, Rothenberg A . Perilipin A and the control of triacylglycerol metabolism . Molecular and Cellular Biochemistry . 326 . 1–2 . 15–21 . June 2009 . 19116774 . 10.1007/s11010-008-9998-8 . 19802945 .
  19. Grahn TH, Zhang Y, Lee MJ, Sommer AG, Mostoslavsky G, Fried SK, Greenberg AS, Puri V . 6 . FSP27 and PLIN1 interaction promotes the formation of large lipid droplets in human adipocytes . Biochemical and Biophysical Research Communications . 432 . 2 . 296–301 . March 2013 . 23399566 . 3595328 . 10.1016/j.bbrc.2013.01.113 .
  20. Web site: Making Fat-proof Mice . Wong K . 2000-11-29 . Scientific American . 2009-05-22.
  21. Sztalryd C, Brasaemle DL . The perilipin family of lipid droplet proteins: Gatekeepers of intracellular lipolysis . Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids . 1862 . 10 Pt B . 1221–1232 . October 2017 . 28754637 . 5595658 . 10.1016/j.bbalip.2017.07.009 .
  22. Bickel PE, Tansey JT, Welte MA . PAT proteins, an ancient family of lipid droplet proteins that regulate cellular lipid stores . Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids . 1791 . 6 . 419–40 . June 2009 . 19375517 . 2782626 . 10.1016/j.bbalip.2009.04.002 .
  23. Soenen S, Mariman EC, Vogels N, Bouwman FG, den Hoed M, Brown L, Westerterp-Plantenga MS. March 2009. Relationship between perilipin gene polymorphisms and body weight and body composition during weight loss and weight maintenance. Physiology & Behavior. 96. 4–5. 723–8. 10.1016/j.physbeh.2009.01.011. 19385027. 24747708.
  24. Yang Y, Fu M, Li MD, Zhang K, Zhang B, Wang S, Liu Y, Ni W, Ong Q, Mi J, Yang X . 6 . O-GlcNAc transferase inhibits visceral fat lipolysis and promotes diet-induced obesity . Nature Communications . 11 . 1 . 181 . January 2020 . 31924761 . 6954210 . 10.1038/s41467-019-13914-8 . 2020NatCo..11..181Y .
  25. telegraph.co.uk, 19 June 2001, News: Couch potato mice discover the lazy way to stay slim . The Daily Telegraph. 2008-09-03 . London . Roger . Highfield . vanc . 2000-11-29.
  26. Tansey JT, Sztalryd C, Gruia-Gray J, Roush DL, Zee JV, Gavrilova O, Reitman ML, Deng CX, Li C, Kimmel AR, Londos C . 6 . Perilipin ablation results in a lean mouse with aberrant adipocyte lipolysis, enhanced leptin production, and resistance to diet-induced obesity . Proceedings of the National Academy of Sciences of the United States of America . 98 . 11 . 6494–9 . May 2001 . 11371650 . 33496 . 10.1073/pnas.101042998 . 2001PNAS...98.6494T . free .
  27. Gandotra S, Le Dour C, Bottomley W, Cervera P, Giral P, Reznik Y, Charpentier G, Auclair M, Delépine M, Barroso I, Semple RK, Lathrop M, Lascols O, Capeau J, O'Rahilly S, Magré J, Savage DB, Vigouroux C . 6 . Perilipin deficiency and autosomal dominant partial lipodystrophy . The New England Journal of Medicine . 364 . 8 . 740–8 . February 2011 . 21345103 . 3773916 . 10.1056/NEJMoa1007487 .
  28. Qi L, Shen H, Larson I, Schaefer EJ, Greenberg AS, Tregouet DA, Corella D, Ordovas JM . 6 . Gender-specific association of a perilipin gene haplotype with obesity risk in a white population . Obesity Research . 12 . 11 . 1758–65 . November 2004 . 15601970 . 10.1038/oby.2004.218 . free .
  29. Corella D, Qi L, Sorlí JV, Godoy D, Portolés O, Coltell O, Greenberg AS, Ordovas JM . 6 . Obese subjects carrying the 11482G>A polymorphism at the perilipin locus are resistant to weight loss after dietary energy restriction . The Journal of Clinical Endocrinology and Metabolism . 90 . 9 . 5121–6 . September 2005 . 15985482 . 10.1210/jc.2005-0576 . free .

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