PNPLA3 explained

Patatin-like phospholipase domain-containing protein 3 (PNPLA3), also known as adiponutrin (ADPN), acylglycerol O-acyltransferase or calcium-independent phospholipase A2-epsilon (iPLA2-epsilon) is an enzyme that in humans is encoded by the PNPLA3 gene.^{[1] [2] [3]}

Function

Adiponutrin is a triacylglycerol lipase that mediates triacylglycerol hydrolysis in adipocytes. The encoded protein, which appears to be membrane bound, may be involved in the balance of energy usage/storage in adipocytes.^[3]

Genomics

The gene is located on the long arm of chromosome 22 at band 13.31 (22q13.31). It lies on the Watson (plus) strand and is 40,750 bases in length.

Upstream of the gene, putative binding sites for several transcription factors have been identified. These include PPAR-gamma, POU2F1, and POU2F2. It is not known at present whether any of these transcriptions factors are actually involved in the regulation of this gene.

Biochemistry

The recommended name for the gene product is patatin-like phospholipase domain-containing protein 3. It is a single-pass type II membrane protein and is a multifunctional enzyme with both triacylglycerol lipase and acylglycerol O-acyltransferase activities. It is involved in the triacylglycerol hydrolysis in adipocytes and may play a role in energy metabolism.

The mature protein is 481 amino acids in length and the predicted molecular weight is 52.865 kilodaltons (kDa). Two of the isoforms have been described, but the functional significance (if any) of these forms is not known.

Clinical relevance

An association between alcoholic liver disease in caucasians and variations in this gene has been confirmed.^[4] A mutation of isoleucine to methionine (I[ATC]>M[ATG]) SNP rs738409 has been confirmed to increase susceptibility to non-alcoholic liver disease and also to have effects in diabetes.^[5]

Further reading

• Dunham I, Shimizu N, Roe BA, Chissoe S, Hunt AR, Collins JE, Bruskiewich R, Beare DM, Clamp M, Smink LJ, Ainscough R, Almeida JP, Babbage A, Bagguley C, Bailey J, Barlow K, Bates KN, Beasley O, Bird CP, Blakey S, Bridgeman AM, Buck D, Burgess J, Burrill WD, O'Brien KP . The DNA sequence of human chromosome 22 . Nature . 402 . 6761 . 489–95 . December 1999 . 10591208 . 10.1038/990031 . 1999Natur.402..489D . free .
• Collins JE, Goward ME, Cole CG, Smink LJ, Huckle EJ, Knowles S, Bye JM, Beare DM, Dunham I . Reevaluating human gene annotation: a second-generation analysis of chromosome 22 . Genome Research . 13 . 1 . 27–36 . January 2003 . 12529303 . 430954 . 10.1101/gr.695703 .
• Liu YM, Moldes M, Bastard JP, Bruckert E, Viguerie N, Hainque B, Basdevant A, Langin D, Pairault J, Clément K . Adiponutrin: A new gene regulated by energy balance in human adipose tissue . The Journal of Clinical Endocrinology and Metabolism . 89 . 6 . 2684–9 . June 2004 . 15181042 . 10.1210/jc.2003-031978 . free .
• Jenkins CM, Mancuso DJ, Yan W, Sims HF, Gibson B, Gross RW . Identification, cloning, expression, and purification of three novel human calcium-independent phospholipase A2 family members possessing triacylglycerol lipase and acylglycerol transacylase activities . The Journal of Biological Chemistry . 279 . 47 . 48968–75 . November 2004 . 15364929 . 10.1074/jbc.M407841200 . free .
• Collins JE, Wright CL, Edwards CA, Davis MP, Grinham JA, Cole CG, Goward ME, Aguado B, Mallya M, Mokrab Y, Huckle EJ, Beare DM, Dunham I . A genome annotation-driven approach to cloning the human ORFeome . Genome Biology . 5 . 10 . R84 . 2005 . 15461802 . 545604 . 10.1186/gb-2004-5-10-r84 . free .
• Lake AC, Sun Y, Li JL, Kim JE, Johnson JW, Li D, Revett T, Shih HH, Liu W, Paulsen JE, Gimeno RE . Expression, regulation, and triglyceride hydrolase activity of Adiponutrin family members . Journal of Lipid Research . 46 . 11 . 2477–87 . November 2005 . 16150821 . 10.1194/jlr.M500290-JLR200 . free .

Notes and References

1. Wilson PA, Gardner SD, Lambie NM, Commans SA, Crowther DJ . Characterization of the human patatin-like phospholipase family . Journal of Lipid Research . 47 . 9 . 1940–9 . September 2006 . 16799181 . 10.1194/jlr.M600185-JLR200 . free .
2. Kienesberger PC, Oberer M, Lass A, Zechner R . Mammalian patatin domain containing proteins: a family with diverse lipolytic activities involved in multiple biological functions . Journal of Lipid Research . 50 Suppl . S63-8 . April 2009 . Suppl . 19029121 . 2674697 . 10.1194/jlr.R800082-JLR200 . free .
3. Web site: Entrez Gene: PNPLA3 patatin-like phospholipase domain containing 3.
4. Stickel F, Hampe J . Genetic determinants of alcoholic liver disease . Gut . 61 . 1 . 150–9 . January 2012 . 22110053 . 10.1136/gutjnl-2011-301239 . 22559086 .
5. Pingitore P, Romeo S . The role of PNPLA3 in health and disease . Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids . 1864 . 6 . 900–906 . June 2019 . 29935383 . 10.1016/j.bbalip.2018.06.018 . 49392249 .