CKDdb-logoCKDdb - Study ID Exp20348205a

PubMed ID20348205
AuthorsAnger GJ, Piquette-Miller M.
TitleImpact of hyperlipidemia on plasma protein binding and hepatic drug transporter and metabolic enzyme regulation in a rat model of gestational diabetes.
JournalJ Pharmacol Exp Ther. 2010 Jul;334(1):21-32.
AbstractIt is currently unknown whether gestational diabetes mellitus (GDM), a prevalent obstetrical complication, compounds the changes in drug disposition that occur naturally in pregnancy. Hyperlipidemia occurs in GDM. Using a rat model of GDM, we determined whether excess lipids compete with drugs for plasma protein binding. Because lipids activate nuclear receptors that regulate drug transporters and metabolic enzymes, we used proteome analysis to determine whether hyperlipidemia indirectly leads to the dysregulation of these proteins in the liver. GDM was induced on gestational day 6 (GD6) via streptozotocin injection. Controls received either vehicle alone or streptozotocin with subsequent insulin treatment. Liver and plasma were collected on GD20. Glyburide and saquinavir protein binding was determined by ultrafiltration, and an established solvent method was used for plasma delipidation. Proteomics analysis was performed by using isobaric tags for relative and absolute quantitation methodology with membrane-enriched hepatic protein samples. Relative to controls, GDM rat plasma contained more cholesterol and triglycerides. Plasma protein binding of glyburide and saquinavir was decreased in GDM. Delipidation normalized protein binding in GDM plasma. Proteins linked to lipid metabolism were strongly affected in the GDM proteomics data set, with prohyperlipidemic and antihyperlipidemic changes observed, and formed networks that implicated several nuclear receptors. Up-regulation of drug transporters and metabolic enzymes was observed (e.g., multidrug resistance 1/2, CYP2A1, CYP2B9, and CYP2D3). In this study, GDM-induced hyperlipidemia decreased protein binding and was associated with drug transporter and metabolic enzyme up-regulation in the liver. Both of these findings could change drug disposition in affected pregnancies, compounding changes associated with pregnancy itself.

Sample characteristics

SpeciesTissue / SourceCompartmentDiseaseNDetection method
Rattus norvegicusbloodplasmaDiabetes10RP-nano-LC-ESI-MS/MS

Sample description and preparation

N (case)5
N (control)5
Disease (case)Gestational Diabetes
Disease (control)healthy, intrap. inj. citrate buffer
Disease inductionsubcutaneous inj. STZ (45 mg/kg)
Preparation specific methodiTRAQ labelling

Molecule list

Molecule IDextExternal IDGeneNameSource accRegulation (case/control)Scores
A6995 MDR3_RATAbcb4, Mdr2, Pgp3Multidrug resistance protein 3Q08201ratio: 1.12
A3582 ACACA_RATAcaca, AcacAcetyl-CoA carboxylase 1P11497ratio: 0.87
A5654 ACADL_RATAcadlLong-chain specific acyl-CoA dehydrogenaseP15650ratio: 1.21
A3694 THIL_RATAcat1Acetyl-CoA acetyltransferaseP17764ratio: 0.85
A3600 AL1A7_RATAldh1a7, Aldh-pb, Aldh1Aldehyde dehydrogenaseP13601ratio: 1.18
A1552 APOA1_RATApoa1Apolipoprotein A-IP04639ratio: 1.17
A0378 ATPB_RATAtp5bATP synthase subunit betaP10719ratio: 0.87
A0391 ATP5J_RATAtp5jATP synthase-coupling factor 6P21571ratio: 0.74
A1598XCO3_RATC3Complement C3P01026ratio: 0.89
A1504 CD36_RATCd36, FatPlatelet glycoprotein 4Q07969ratio: 0.8
A7121 NB5R3_RATCyb5r3, Dia1NADH-cytochrome b5 reductase 3P20070ratio: 0.85
A6182 CP4AA_RATCyp4a10, Cyp4a-1, Cyp4a1Cytochrome P450 4A10P08516ratio: 1.28
A6185XCP4AE_RATCyp4a14, Cyp4a-3, Cyp4a3Cytochrome P450 4A14P20817ratio: 1.38
A6195XCP51A_RATCyp51a1, Cyp51Lanosterol 14-alpha demethylaseQ64654ratio: 1.2
A6410 ECI1_RATEci1, DciEnoyl-CoA delta isomerase 1P23965ratio: 1.34
A3699 DECR_RATDecr1, Decr2,4-dienoyl CoA reductase 1, mitochondrialQ64591ratio: 1.12
A3584XFAS_RATFasnFatty acid synthaseP12785ratio: 0.82
A6504 FDFT_RATFdft1Squalene synthaseQ02769ratio: 1.12
A6522 FPPS_RATFdpsFarnesyl pyrophosphate synthaseP05369ratio: 0.88
A6547XG6PC_RATG6pc, G6ptGlucose-6-phosphataseP43428ratio: 1.68
A7957XTECR_RATTecr, Gpsn2Very-long-chain enoyl-CoA reductaseQ64232ratio: 0.85
A0486 HMOX1_RATHmox1Heme oxygenase 1P06762ratio: 0.84
A530C SO1A1_RATSlco1a1, Oatp1, Oatp1a1Solute carrier organic anion transporter family member 1A1P46720ratio: 0.88
A350C RET1_RATRbp1, Rbp-1Retinol-binding protein 1P02696ratio: 0.86
A7674XRETST_RATRetsat, Ppsig, Rmt7All-trans-retinol 13Q8VHE9ratio: 1.29
A9019 RHOA_RATRhoa, Arha, Arha2Transforming protein RhoA ( Precursor)P61589ratio: 1.13
A8369XA1AT_RATSerpina1Alpha-1-antiproteinaseP17475ratio: 1.16
A7767 S27A2_RATSlc27a2, Acsvl1, Facvl1Very long-chain acyl-CoA synthetaseP97524ratio: 1.21
A7770 S27A5_RATSlc27a5, Acsb, Fatp5Bile acyl-CoA synthetaseQ9ES38ratio: 1.37
A7771XS5A1_RATSrd5a13-oxo-5-alpha-steroid 4-dehydrogenase 1P24008ratio: 0.81
A7809 SIA10_RATSt3gal6, Siat10Type 2 lactosamine alpha-2P61943ratio: 0.77
A8145 UD11_RATUgt1a1, Ugt1UDP-glucuronosyltransferase 1-1Q64550ratio: 1.3

Compile date 08-10-2018© iMODE-CKD consortium