Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDF8R2M)

• DOT Name: Glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1)
• Synonyms: GPI-HBP1; GPI-anchored HDL-binding protein 1; High density lipoprotein-binding protein 1
• Gene Name: GPIHBP1
• Related Disease:
  Non-insulin dependent diabetes
  Arteriosclerosis
  Atherosclerosis
  Colitis
  Coronary atherosclerosis
  Familial lipoprotein lipase deficiency
  Glioma
  Hyperlipidemia
  Hyperlipoproteinemia
  Hyperlipoproteinemia, type 1D
  Hypertriglyceridemia
  Obesity
  Type-1/2 diabetes
  Cardiovascular disease
  Metabolic disorder
  Chronic pancreatitis
  Coronary heart disease
  Pancreatitis
• UniProt ID: HDBP1_HUMAN
• PDB ID: 6E7K; 6OAU; 6OAZ; 6OB0
• Pfam ID: PF00021
• Sequence:
  MKALGAVLLALLLFGRPGRGQTQQEEEEEDEDHGPDDYDEEDEDEVEEEETNRLPGGRSR
  VLLRCYTCKSLPRDERCNLTQNCSHGQTCTTLIAHGNTESGLLTTHSTWCTDSCQPITKT
  VEGTQVTMTCCQSSLCNVPPWQSSRVQDPTGKGAGGPRGSSETVGAALLLNLLAGLGAMG
  ARRP
• Function: Mediates the transport of lipoprotein lipase LPL from the basolateral to the apical surface of endothelial cells in capillaries. Anchors LPL on the surface of endothelial cells in the lumen of blood capillaries. Protects LPL against loss of activity, and against ANGPTL4-mediated unfolding. Thereby, plays an important role in lipolytic processing of chylomicrons by LPL, triglyceride metabolism and lipid homeostasis. Binds chylomicrons and phospholipid particles that contain APOA5. Binds high-density lipoprotein (HDL) and plays a role in the uptake of lipids from HDL.
• Reactome Pathway:
  Assembly of active LPL and LIPC lipase complexes (R-HSA-8963889)
  Chylomicron remodeling (R-HSA-8963901)
  Retinoid metabolism and transport (R-HSA-975634)
  Post-translational modification (R-HSA-163125)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Altered Expression	[1]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[2]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[2]
Colitis	DISAF7DD	Strong	Genetic Variation	[3]
Coronary atherosclerosis	DISKNDYU	Strong	Biomarker	[4]
Familial lipoprotein lipase deficiency	DIS0M7NJ	Strong	Genetic Variation	[5]
Glioma	DIS5RPEH	Strong	Biomarker	[6]
Hyperlipidemia	DIS61J3S	Strong	Biomarker	[7]
Hyperlipoproteinemia	DISVBLBO	Strong	Genetic Variation	[8]
Hyperlipoproteinemia, type 1D	DISOG6KW	Strong	Autosomal recessive	[9]
Hypertriglyceridemia	DIS7SN6U	Strong	CausalMutation	[3]
Obesity	DIS47Y1K	Strong	Biomarker	[10]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[2]
Cardiovascular disease	DIS2IQDX	moderate	Biomarker	[11]
Metabolic disorder	DIS71G5H	moderate	Altered Expression	[11]
Chronic pancreatitis	DISBUOMJ	Limited	Genetic Variation	[8]
Coronary heart disease	DIS5OIP1	Limited	Biomarker	[4]
Pancreatitis	DIS0IJEF	Limited	Genetic Variation	[12]

3 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 Glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1).	[13]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1).	[16]

1 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1).	[15]

References

• [1] Decreased GPIHBP1 protein levels in visceral adipose tissue partly underlie the hypertriglyceridemic phenotype in insulin resistance.PLoS One. 2018 Nov 8;13(11):e0205858. doi: 10.1371/journal.pone.0205858. eCollection 2018.
• [2] Gpihbp1 deficiency accelerates atherosclerosis and plaque instability in diabetic Ldlr(-/-) mice.Atherosclerosis. 2019 Mar;282:100-109. doi: 10.1016/j.atherosclerosis.2019.01.025. Epub 2019 Jan 29.
• [3] Whole-exome sequencing reveals GPIHBP1 mutations in infantile colitis with severe hypertriglyceridemia.J Pediatr Gastroenterol Nutr. 2014 Jul;59(1):17-21. doi: 10.1097/MPG.0000000000000363.
• [4] The role of plasma lipoprotein lipase, hepatic lipase and GPIHBP1 in the metabolism of remnant lipoproteins and small dense LDL in patients with coronary artery disease.Clin Chim Acta. 2018 Jan;476:146-153. doi: 10.1016/j.cca.2017.11.021. Epub 2017 Nov 22.
• [5] A novel mutation in GPIHBP1 causes familial chylomicronemia syndrome.J Clin Lipidol. 2018 Mar-Apr;12(2):506-510. doi: 10.1016/j.jacl.2018.01.011. Epub 2018 Jan 31.
• [6] GPIHBP1 expression in gliomas promotes utilization of lipoprotein-derived nutrients.Elife. 2019 Jun 6;8:e47178. doi: 10.7554/eLife.47178.
• [7] A novel lipoprotein lipase gene missense mutation in Chinese patients with severe hypertriglyceridemia and pancreatitis.Lipids Health Dis. 2014 Mar 19;13:52. doi: 10.1186/1476-511X-13-52.
• [8] Homozygous missense mutation (G56R) in glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPI-HBP1) in two siblings with fasting chylomicronemia (MIM 144650).Lipids Health Dis. 2007 Sep 20;6:23. doi: 10.1186/1476-511X-6-23.
• [9] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [10] The effect of combined diet and exercise intervention on body weight and the serum GPIHBP1 concentration in overweight/obese middle-aged women.Clin Chim Acta. 2017 Dec;475:109-115. doi: 10.1016/j.cca.2017.10.017. Epub 2017 Oct 19.
• [11] An enzyme-linked immunosorbent assay for measuring GPIHBP1 levels in human plasma orserum.J Clin Lipidol. 2018 Jan-Feb;12(1):203-210.e1. doi: 10.1016/j.jacl.2017.10.022. Epub 2017 Nov 1.
• [12] Extreme hypertriglyceridemia: Genetic diversity, pancreatitis, pregnancy, and prevalence.J Clin Lipidol. 2019 Jan-Feb;13(1):89-99. doi: 10.1016/j.jacl.2018.09.007. Epub 2018 Sep 18.
• [13] 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.
• [14] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] 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.