Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTR3ERMR)

DOT Name Patatin-like phospholipase domain-containing protein 2 (PNPLA2)
Synonyms
EC 3.1.1.3; Adipose triglyceride lipase; Calcium-independent phospholipase A2-zeta; iPLA2-zeta; EC 3.1.1.4; Desnutrin; Pigment epithelium-derived factor receptor; PEDF-R; TTS2.2; Transport-secretion protein 2; TTS2
Gene Name PNPLA2
Related Disease
Hemangioma ( )
Neutral lipid storage myopathy ( )
Retinopathy ( )
Advanced cancer ( )
Age-related macular degeneration ( )
Alzheimer disease ( )
Arteriosclerosis ( )
Atherosclerosis ( )
Cardiac disease ( )
Cardiac failure ( )
Cardiomyopathy ( )
Cardiovascular disease ( )
Colon cancer ( )
Colon carcinoma ( )
Congestive heart failure ( )
Diabetic kidney disease ( )
Diabetic retinopathy ( )
Dorfman-Chanarin disease ( )
Epithelial ovarian cancer ( )
Fatty liver disease ( )
Hepatocellular carcinoma ( )
Liposarcoma ( )
Lung cancer ( )
Metabolic disorder ( )
Myopathy ( )
Neoplasm ( )
Non-alcoholic steatohepatitis ( )
Non-insulin dependent diabetes ( )
Non-syndromic ichthyosis ( )
Osteogenesis imperfecta ( )
Osteogenesis imperfecta type 6 ( )
Ovarian cancer ( )
Ovarian neoplasm ( )
Polycystic ovarian syndrome ( )
Prostate cancer ( )
Prostate carcinoma ( )
Stomach cancer ( )
Type-1/2 diabetes ( )
Melanoma ( )
Metastatic malignant neoplasm ( )
Breast cancer ( )
Breast carcinoma ( )
Colorectal carcinoma ( )
Glioma ( )
Lung carcinoma ( )
Nasopharyngeal carcinoma ( )
UniProt ID
PLPL2_HUMAN
3D Structure
Download
2D Sequence (FASTA)
Download
3D Structure (PDB)
Download
EC Number
3.1.1.3; 3.1.1.4
Pfam ID
PF01734
Sequence
MFPREKTWNISFAGCGFLGVYYVGVASCLREHAPFLVANATHIYGASAGALTATALVTGV
CLGEAGAKFIEVSKEARKRFLGPLHPSFNLVKIIRSFLLKVLPADSHEHASGRLGISLTR
VSDGENVIISHFNSKDELIQANVCSGFIPVYCGLIPPSLQGVRYVDGGISDNLPLYELKN
TITVSPFSGESDICPQDSSTNIHELRVTNTSIQFNLRNLYRLSKALFPPEPLVLREMCKQ
GYRDGLRFLQRNGLLNRPNPLLALPPARPHGPEDKDQAVESAQAEDYSQLPGEDHILEHL
PARLNEALLEACVEPTDLLTTLSNMLPVRLATAMMVPYTLPLESALSFTIRLLEWLPDVP
EDIRWMKEQTGSICQYLVMRAKRKLGRHLPSRLPEQVELRRVQSLPSVPLSCAAYREALP
GWMRNNLSLGDALAKWEECQRQLLLGLFCTNVAFPPEALRMRAPADPAPAPADPASPQHQ
LAGPAPLLSTPAPEARPVIGALGL
Function
Catalyzes the initial step in triglyceride hydrolysis in adipocyte and non-adipocyte lipid droplets. Exhibits a strong preference for the hydrolysis of long-chain fatty acid esters at the sn-2 position of the glycerol backbone and acts coordinately with LIPE/HLS and DGAT2 within the lipolytic cascade. Also possesses acylglycerol transacylase and phospholipase A2 activities. Transfers fatty acid from triglyceride to retinol, hydrolyzes retinylesters, and generates 1,3-diacylglycerol from triglycerides. Regulates adiposome size and may be involved in the degradation of adiposomes. May play an important role in energy homeostasis. May play a role in the response of the organism to starvation, enhancing hydrolysis of triglycerides and providing free fatty acids to other tissues to be oxidized in situations of energy depletion. Catalyzes the formation of an ester bond between hydroxy fatty acids and fatty acids derived from triglycerides or diglycerides to generate fatty acid esters of hydroxy fatty acids (FAHFAs) in adipocytes.
Tissue Specificity
Highest expression in adipose tissue. Also detected in heart, skeletal muscle, and portions of the gastrointestinal tract. Detected in normal retina and retinoblastoma cells. Detected in retinal pigment epithelium and, at lower intensity, in the inner segments of photoreceptors and in the ganglion cell layer of the neural retina (at protein level).
KEGG Pathway
Glycerolipid metabolism (hsa00561 )
Metabolic pathways (hsa01100 )
Thermogenesis (hsa04714 )
Regulation of lipolysis in adipocytes (hsa04923 )
Reactome Pathway
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426 )
Post-translational protein phosphorylation (R-HSA-8957275 )
Acyl chain remodeling of DAG and TAG (R-HSA-1482883 )

Molecular Interaction Atlas (MIA) of This DOT

46 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Hemangioma DISDCGAG Definitive Biomarker [1]
Neutral lipid storage myopathy DISR9UYD Definitive Autosomal recessive [2]
Retinopathy DISB4B0F Definitive Altered Expression [3]
Advanced cancer DISAT1Z9 Strong Biomarker [4]
Age-related macular degeneration DIS0XS2C Strong Biomarker [5]
Alzheimer disease DISF8S70 Strong Biomarker [6]
Arteriosclerosis DISK5QGC Strong Biomarker [7]
Atherosclerosis DISMN9J3 Strong Biomarker [7]
Cardiac disease DISVO1I5 Strong Genetic Variation [8]
Cardiac failure DISDC067 Strong Biomarker [9]
Cardiomyopathy DISUPZRG Strong Genetic Variation [10]
Cardiovascular disease DIS2IQDX Strong Genetic Variation [11]
Colon cancer DISVC52G Strong Biomarker [12]
Colon carcinoma DISJYKUO Strong Biomarker [12]
Congestive heart failure DIS32MEA Strong Biomarker [9]
Diabetic kidney disease DISJMWEY Strong Altered Expression [13]
Diabetic retinopathy DISHGUJM Strong Altered Expression [14]
Dorfman-Chanarin disease DISKKT3R Strong Genetic Variation [15]
Epithelial ovarian cancer DIS56MH2 Strong Biomarker [16]
Fatty liver disease DIS485QZ Strong Altered Expression [17]
Hepatocellular carcinoma DIS0J828 Strong Altered Expression [18]
Liposarcoma DIS8IZVM Strong Biomarker [19]
Lung cancer DISCM4YA Strong Biomarker [20]
Metabolic disorder DIS71G5H Strong Biomarker [21]
Myopathy DISOWG27 Strong Genetic Variation [15]
Neoplasm DISZKGEW Strong Biomarker [22]
Non-alcoholic steatohepatitis DIST4788 Strong Biomarker [23]
Non-insulin dependent diabetes DISK1O5Z Strong Biomarker [24]
Non-syndromic ichthyosis DISZ9QBQ Strong Biomarker [25]
Osteogenesis imperfecta DIS7XQSD Strong Biomarker [26]
Osteogenesis imperfecta type 6 DIS0ZNUU Strong Genetic Variation [27]
Ovarian cancer DISZJHAP Strong Biomarker [16]
Ovarian neoplasm DISEAFTY Strong Biomarker [16]
Polycystic ovarian syndrome DISZ2BNG Strong Altered Expression [28]
Prostate cancer DISF190Y Strong Biomarker [29]
Prostate carcinoma DISMJPLE Strong Biomarker [29]
Stomach cancer DISKIJSX Strong Biomarker [30]
Type-1/2 diabetes DISIUHAP Strong Genetic Variation [31]
Melanoma DIS1RRCY moderate Biomarker [32]
Metastatic malignant neoplasm DIS86UK6 moderate Biomarker [33]
Breast cancer DIS7DPX1 Limited Altered Expression [34]
Breast carcinoma DIS2UE88 Limited Altered Expression [34]
Colorectal carcinoma DIS5PYL0 Limited Biomarker [35]
Glioma DIS5RPEH Limited Altered Expression [36]
Lung carcinoma DISTR26C Limited Biomarker [20]
Nasopharyngeal carcinoma DISAOTQ0 Limited Biomarker [37]
------------------------------------------------------------------------------------
⏷ Show the Full List of 46 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
2 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate increases the methylation of Patatin-like phospholipase domain-containing protein 2 (PNPLA2). [38]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene decreases the methylation of Patatin-like phospholipase domain-containing protein 2 (PNPLA2). [45]
------------------------------------------------------------------------------------
9 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Estradiol DMUNTE3 Approved Estradiol affects the expression of Patatin-like phospholipase domain-containing protein 2 (PNPLA2). [39]
Dexamethasone DMMWZET Approved Dexamethasone increases the expression of Patatin-like phospholipase domain-containing protein 2 (PNPLA2). [40]
Hydrocortisone DMGEMB7 Approved Hydrocortisone decreases the expression of Patatin-like phospholipase domain-containing protein 2 (PNPLA2). [41]
Urethane DM7NSI0 Phase 4 Urethane increases the expression of Patatin-like phospholipase domain-containing protein 2 (PNPLA2). [42]
GSK2110183 DMZHB37 Phase 2 GSK2110183 increases the expression of Patatin-like phospholipase domain-containing protein 2 (PNPLA2). [43]
Beta-caryophyllene DM7583A Phase 2 Beta-caryophyllene increases the expression of Patatin-like phospholipase domain-containing protein 2 (PNPLA2). [44]
(+)-JQ1 DM1CZSJ Phase 1 (+)-JQ1 increases the expression of Patatin-like phospholipase domain-containing protein 2 (PNPLA2). [46]
Bisphenol A DM2ZLD7 Investigative Bisphenol A increases the expression of Patatin-like phospholipase domain-containing protein 2 (PNPLA2). [47]
D-glucose DMMG2TO Investigative D-glucose decreases the expression of Patatin-like phospholipase domain-containing protein 2 (PNPLA2). [48]
------------------------------------------------------------------------------------
⏷ Show the Full List of 9 Drug(s)

References

1 Pigment epithelium-derived factor/vascular endothelial growth factor ratio plays a crucial role in the spontaneous regression of infant hemangioma and in the therapeutic effect of propranolol.Cancer Sci. 2018 Jun;109(6):1981-1994. doi: 10.1111/cas.13611. Epub 2018 May 23.
2 Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
3 Opioid Receptor Agonism Preserves the Retinal Pigmented Epithelial Cell Tight Junctions and Ameliorates the Retinopathy in Experimental Diabetes.Invest Ophthalmol Vis Sci. 2019 Sep 3;60(12):3842-3853. doi: 10.1167/iovs.19-26761.
4 Therapeutic Potential of Pigment Epithelium-derived Factor in Cancer.Curr Pharm Des. 2019;25(3):313-324. doi: 10.2174/1381612825666190319112106.
5 Negative regulators of angiogenesis: important targets for treatment of exudative AMD.Clin Sci (Lond). 2017 Jul 5;131(15):1763-1780. doi: 10.1042/CS20170066. Print 2017 Aug 1.
6 Pigment Epithelium-Derived Factor Plays a Role in Alzheimer's Disease by Negatively Regulating A42.Neurotherapeutics. 2018 Jul;15(3):728-741. doi: 10.1007/s13311-018-0628-1.
7 LncRNA SRA deregulation contributes to the development of atherosclerosis by causing dysfunction of endothelial cells through repressing the expression of adipose triglyceride lipase.Mol Med Rep. 2018 Dec;18(6):5207-5214. doi: 10.3892/mmr.2018.9497. Epub 2018 Sep 20.
8 Symptomatic lipid storage in carriers for the PNPLA2 gene.Eur J Hum Genet. 2013 Aug;21(8):807-15. doi: 10.1038/ejhg.2012.256. Epub 2012 Dec 12.
9 Adipose tissue ATGL modifies the cardiac lipidome in pressure-overload-induced left ventricular failure.PLoS Genet. 2018 Jan 10;14(1):e1007171. doi: 10.1371/journal.pgen.1007171. eCollection 2018 Jan.
10 The homozygous variant c.245G > A/p.G82D in PNPLA2 is associated with arrhythmogenic cardiomyopathy phenotypic manifestations.Clin Genet. 2019 Dec;96(6):532-540. doi: 10.1111/cge.13642. Epub 2019 Oct 23.
11 Effect of Bariatric Weight Loss on the Adipose Lipolytic Transcriptome in Obese Humans.Mediators Inflamm. 2015;2015:106237. doi: 10.1155/2015/106237. Epub 2015 Nov 18.
12 ABHD5 interacts with BECN1 to regulate autophagy and tumorigenesis of colon cancer independent of PNPLA2.Autophagy. 2016 Nov;12(11):2167-2182. doi: 10.1080/15548627.2016.1217380. Epub 2016 Aug 25.
13 Diabetic nephropathy: serum miR-9 confers a poor prognosis in and is associated with level changes of vascular endothelial growth factor and pigment epithelium-derived factor.Biotechnol Lett. 2017 Oct;39(10):1583-1590. doi: 10.1007/s10529-017-2390-6. Epub 2017 Jun 30.
14 Antiangiogenic effects and transcriptional regulation of pigment epithelium-derived factor in diabetic retinopathy.Microvasc Res. 2010 Jul;80(1):31-6. doi: 10.1016/j.mvr.2010.02.012. Epub 2010 Feb 26.
15 Late onset of neutral lipid storage disease due to novel PNPLA2 mutations causing total loss of lipase activity in a patient with myopathy and slight cardiac involvement.Neuromuscul Disord. 2017 May;27(5):481-486. doi: 10.1016/j.nmd.2017.01.011. Epub 2017 Jan 17.
16 The reduction in pigment epithelium-derived factor is a sign of malignancy in ovarian cancer expressing low-level of vascular endothelial growth factor.Gynecol Endocrinol. 2009 Feb;25(2):104-9. doi: 10.1080/09513590802549841.
17 Adipose tissue deficiency of hormone-sensitive lipase causes fatty liver in mice.PLoS Genet. 2017 Dec 12;13(12):e1007110. doi: 10.1371/journal.pgen.1007110. eCollection 2017 Dec.
18 PNPLA3, CGI-58, and Inhibition of Hepatic Triglyceride Hydrolysis in Mice.Hepatology. 2019 Jun;69(6):2427-2441. doi: 10.1002/hep.30583. Epub 2019 Apr 9.
19 Epistatic interaction between the lipase-encoding genes Pnpla2 and Lipe causes liposarcoma in mice.PLoS Genet. 2017 May 1;13(5):e1006716. doi: 10.1371/journal.pgen.1006716. eCollection 2017 May.
20 Pigment epithelium-derived factor inhibits lung cancer migration and invasion by upregulating exosomal thrombospondin 1.Cancer Lett. 2019 Feb 1;442:287-298. doi: 10.1016/j.canlet.2018.10.031. Epub 2018 Nov 12.
21 Pigment epithelium-derived factor inhibits adipogenesis in 3T3-L1 adipocytes and protects against high-fat diet-induced obesity and metabolic disorders in mice.Transl Res. 2019 Aug;210:26-42. doi: 10.1016/j.trsl.2019.04.006. Epub 2019 May 3.
22 Hints on ATGL implications in cancer: beyond bioenergetic clues.Cell Death Dis. 2018 Feb 22;9(3):316. doi: 10.1038/s41419-018-0345-z.
23 iPla2 deficiency in mice fed with MCD diet does not correct the defect of phospholipid remodeling but attenuates hepatocellular injury via an inhibition of lipid uptake genes.Biochim Biophys Acta Mol Cell Biol Lipids. 2019 May;1864(5):677-687. doi: 10.1016/j.bbalip.2019.02.003. Epub 2019 Feb 5.
24 Association of pigment epithelium derived factor with von Willebrand factor and plasminogen activator inhibitor 1 in patients with type 2 diabetes.Physiol Res. 2019 Jun 30;68(3):409-418. doi: 10.33549/physiolres.934013. Epub 2019 Mar 22.
25 Inborn errors of cytoplasmic triglyceride metabolism.J Inherit Metab Dis. 2015 Jan;38(1):85-98. doi: 10.1007/s10545-014-9767-7. Epub 2014 Oct 10.
26 Novel mutations of the SERPINF1 and FKBP10 genes in Chinese families with autosomal recessive osteogenesis imperfecta.Int J Mol Med. 2018 Jun;41(6):3662-3670. doi: 10.3892/ijmm.2018.3542. Epub 2018 Mar 7.
27 Pigment epithelium-derived factor (PEDF) reduced expression and synthesis of SOST/sclerostin in bone explant cultures: implication of PEDF-osteocyte gene regulation in vivo.J Bone Miner Metab. 2019 Sep;37(5):773-779. doi: 10.1007/s00774-018-0982-4. Epub 2019 Jan 3.
28 Circulating levels and subcutaneous adipose tissue gene expression of pigment epithelium-derived factor in polycystic ovary syndrome and normal women: a case control study.Reprod Biol Endocrinol. 2013 Aug 14;11:77. doi: 10.1186/1477-7827-11-77.
29 Loss of ABHD5 promotes the aggressiveness of prostate cancer cells.Sci Rep. 2017 Oct 12;7(1):13021. doi: 10.1038/s41598-017-13398-w.
30 Pigment epithelium-derived factor inhibits angiogenesis and growth of gastric carcinoma by down-regulation of VEGF.Oncol Rep. 2011 Sep;26(3):681-6. doi: 10.3892/or.2011.1318. Epub 2011 May 25.
31 Newly developed selective immunoinactivation assay revealed reduction in adipose triglyceride lipase activity in peripheral leucocytes from patients with idiopathic triglyceride deposit cardiomyovasculopathy.Biochem Biophys Res Commun. 2018 Jan 1;495(1):646-651. doi: 10.1016/j.bbrc.2017.11.070. Epub 2017 Nov 13.
32 Regulatory and functional connection of microphthalmia-associated transcription factor and anti-metastatic pigment epithelium derived factor in melanoma.Neoplasia. 2014 Jun;16(6):529-42. doi: 10.1016/j.neo.2014.06.001. Epub 2014 Jul 13.
33 Pigment epithelium-derived factor promotes tumor metastasis through an interaction with laminin receptor in hepatocellular carcinomas.Cell Death Dis. 2017 Aug 3;8(8):e2969. doi: 10.1038/cddis.2017.359.
34 Utilization of adipocyte-derived lipids and enhanced intracellular trafficking of fatty acids contribute to breast cancer progression.Cell Commun Signal. 2018 Jun 18;16(1):32. doi: 10.1186/s12964-018-0221-6.
35 Impact of pigment epithelium-derived factor on colorectal cancer in vitro and in vivo.Oncotarget. 2018 Apr 10;9(27):19192-19202. doi: 10.18632/oncotarget.24953. eCollection 2018 Apr 10.
36 Loss of pigment epithelium derived factor expression in glioma progression.J Clin Pathol. 2003 Apr;56(4):277-82. doi: 10.1136/jcp.56.4.277.
37 Correction: Deficiency of pigment epithelium-derived factor in nasopharyngeal carcinoma cells triggers the epithelial-mesenchymal transition and metastasis.Cell Death Dis. 2018 Jul 16;9(8):784. doi: 10.1038/s41419-018-0829-x.
38 Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
39 Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
40 Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
41 Prenatal caffeine exposure increases the susceptibility to non-alcoholic fatty liver disease in female offspring rats via activation of GR-C/EBP-SIRT1 pathway. Toxicology. 2019 Apr 1;417:23-34. doi: 10.1016/j.tox.2019.02.008. Epub 2019 Feb 15.
42 Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
43 Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
44 -Caryophyllene attenuates palmitate-induced lipid accumulation through AMPK signaling by activating CB2 receptor in human HepG2 hepatocytes. Mol Nutr Food Res. 2016 Oct;60(10):2228-2242. doi: 10.1002/mnfr.201600197. Epub 2016 Jun 16.
45 Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
46 Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
47 Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
48 Calorie restriction-induced changes in the secretome of human adipocytes, comparison with resveratrol-induced secretome effects. Biochim Biophys Acta. 2014 Sep;1844(9):1511-22. doi: 10.1016/j.bbapap.2014.04.023. Epub 2014 May 5.