Increased Levels of Fatty Acids Contributed to Induction of Hepatic CYP3A4 Activity Induced by Diabetes — In Vitro Evidence From HepG2 Cell and Fa2N-4 Cell Lines

Accumulating evidences have shown that diabetes upregulated the function and expression of CYP3A4, but the mechanism remained unclear. In this study, HepG2 cells were incubated with serum from diabetic rats induced by streptozotocin, and the activity of CYP3A4 was measured by substrate metabolism. R...

Full description

Bibliographic Details
Main Authors:	Nan Hu, Mengyue Hu, Ru Duan, Can Liu, Haifang Guo, Mian Zhang, Yunli Yu, Xinting Wang, Li Liu, Xiaodong Liu
Format:	Article
Language:	English
Published:	Elsevier 2014-01-01
Series:	Journal of Pharmacological Sciences
Online Access:	http://www.sciencedirect.com/science/article/pii/S1347861319301665

id	doaj-52c90b87f8de4ff1b3fc6638dad2250e
record_format	Article
spelling	doaj-52c90b87f8de4ff1b3fc6638dad2250e2020-11-25T01:22:40ZengElsevierJournal of Pharmacological Sciences1347-86132014-01-011244433444Increased Levels of Fatty Acids Contributed to Induction of Hepatic CYP3A4 Activity Induced by Diabetes — In Vitro Evidence From HepG2 Cell and Fa2N-4 Cell LinesNan Hu0Mengyue Hu1Ru Duan2Can Liu3Haifang Guo4Mian Zhang5Yunli Yu6Xinting Wang7Li Liu8Xiaodong Liu9Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210000, Jiangsu, China; Department of Clinical Pharmacy, The Third Affiliated Hospital of Soochow University, Changzhou 213000, Jiangsu, ChinaKey Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210000, Jiangsu, ChinaKey Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210000, Jiangsu, ChinaKey Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210000, Jiangsu, ChinaKey Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210000, Jiangsu, ChinaKey Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210000, Jiangsu, ChinaKey Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210000, Jiangsu, ChinaKey Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210000, Jiangsu, ChinaKey Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210000, Jiangsu, China; Corresponding authors. aliulee@yeah.net, bxdliu@cpu.edu.cnKey Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210000, Jiangsu, China; Corresponding authors. aliulee@yeah.net, bxdliu@cpu.edu.cnAccumulating evidences have shown that diabetes upregulated the function and expression of CYP3A4, but the mechanism remained unclear. In this study, HepG2 cells were incubated with serum from diabetic rats induced by streptozotocin, and the activity of CYP3A4 was measured by substrate metabolism. Results showed that incubation with diabetic serum significantly induced CYP3A4 activity in HepG2 cells. To identify the specific factors contributing to the regulation, the abnormally altered components in diabetic serum, including glucose, insulin, cholesterol, and free fatty acids were screened. It was found that only fatty acids concentration-dependently up-regulated CYP3A4 activity, and the induction by fatty acids was further confirmed in Fa2N-4 cells. Data from western blotting and QT-PCR showed that induction of CYP3A4 activity was associated with up-regulation of CYP3A4 protein and mRNA levels. In addition, effects of pharmacological inhibitors on fatty acid–induced CYP3A4 activity were studied. The results indicated that the induction of CYP3A4 activity by oleic acid may be partly via AMPK-, PKC-, and NF-κB–dependent pathways, whereas that by palmitic acid was possibly associated with the PKC-dependent pathway. In conclusion, the increased levels of fatty acids may be one of the reasons leading to the elevated function and expression of CYP3A4 under diabetic conditions. Keywords:: diabetes, fatty acid, CYP3A4, HepG2, Fa2N-4http://www.sciencedirect.com/science/article/pii/S1347861319301665
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Nan Hu Mengyue Hu Ru Duan Can Liu Haifang Guo Mian Zhang Yunli Yu Xinting Wang Li Liu Xiaodong Liu
spellingShingle	Nan Hu Mengyue Hu Ru Duan Can Liu Haifang Guo Mian Zhang Yunli Yu Xinting Wang Li Liu Xiaodong Liu Increased Levels of Fatty Acids Contributed to Induction of Hepatic CYP3A4 Activity Induced by Diabetes — In Vitro Evidence From HepG2 Cell and Fa2N-4 Cell Lines Journal of Pharmacological Sciences
author_facet	Nan Hu Mengyue Hu Ru Duan Can Liu Haifang Guo Mian Zhang Yunli Yu Xinting Wang Li Liu Xiaodong Liu
author_sort	Nan Hu
title	Increased Levels of Fatty Acids Contributed to Induction of Hepatic CYP3A4 Activity Induced by Diabetes — In Vitro Evidence From HepG2 Cell and Fa2N-4 Cell Lines
title_short	Increased Levels of Fatty Acids Contributed to Induction of Hepatic CYP3A4 Activity Induced by Diabetes — In Vitro Evidence From HepG2 Cell and Fa2N-4 Cell Lines
title_full	Increased Levels of Fatty Acids Contributed to Induction of Hepatic CYP3A4 Activity Induced by Diabetes — In Vitro Evidence From HepG2 Cell and Fa2N-4 Cell Lines
title_fullStr	Increased Levels of Fatty Acids Contributed to Induction of Hepatic CYP3A4 Activity Induced by Diabetes — In Vitro Evidence From HepG2 Cell and Fa2N-4 Cell Lines
title_full_unstemmed	Increased Levels of Fatty Acids Contributed to Induction of Hepatic CYP3A4 Activity Induced by Diabetes — In Vitro Evidence From HepG2 Cell and Fa2N-4 Cell Lines
title_sort	increased levels of fatty acids contributed to induction of hepatic cyp3a4 activity induced by diabetes — in vitro evidence from hepg2 cell and fa2n-4 cell lines
publisher	Elsevier
series	Journal of Pharmacological Sciences
issn	1347-8613
publishDate	2014-01-01
description	Accumulating evidences have shown that diabetes upregulated the function and expression of CYP3A4, but the mechanism remained unclear. In this study, HepG2 cells were incubated with serum from diabetic rats induced by streptozotocin, and the activity of CYP3A4 was measured by substrate metabolism. Results showed that incubation with diabetic serum significantly induced CYP3A4 activity in HepG2 cells. To identify the specific factors contributing to the regulation, the abnormally altered components in diabetic serum, including glucose, insulin, cholesterol, and free fatty acids were screened. It was found that only fatty acids concentration-dependently up-regulated CYP3A4 activity, and the induction by fatty acids was further confirmed in Fa2N-4 cells. Data from western blotting and QT-PCR showed that induction of CYP3A4 activity was associated with up-regulation of CYP3A4 protein and mRNA levels. In addition, effects of pharmacological inhibitors on fatty acid–induced CYP3A4 activity were studied. The results indicated that the induction of CYP3A4 activity by oleic acid may be partly via AMPK-, PKC-, and NF-κB–dependent pathways, whereas that by palmitic acid was possibly associated with the PKC-dependent pathway. In conclusion, the increased levels of fatty acids may be one of the reasons leading to the elevated function and expression of CYP3A4 under diabetic conditions. Keywords:: diabetes, fatty acid, CYP3A4, HepG2, Fa2N-4
url	http://www.sciencedirect.com/science/article/pii/S1347861319301665
work_keys_str_mv	AT nanhu increasedlevelsoffattyacidscontributedtoinductionofhepaticcyp3a4activityinducedbydiabetesinvitroevidencefromhepg2cellandfa2n4celllines AT mengyuehu increasedlevelsoffattyacidscontributedtoinductionofhepaticcyp3a4activityinducedbydiabetesinvitroevidencefromhepg2cellandfa2n4celllines AT ruduan increasedlevelsoffattyacidscontributedtoinductionofhepaticcyp3a4activityinducedbydiabetesinvitroevidencefromhepg2cellandfa2n4celllines AT canliu increasedlevelsoffattyacidscontributedtoinductionofhepaticcyp3a4activityinducedbydiabetesinvitroevidencefromhepg2cellandfa2n4celllines AT haifangguo increasedlevelsoffattyacidscontributedtoinductionofhepaticcyp3a4activityinducedbydiabetesinvitroevidencefromhepg2cellandfa2n4celllines AT mianzhang increasedlevelsoffattyacidscontributedtoinductionofhepaticcyp3a4activityinducedbydiabetesinvitroevidencefromhepg2cellandfa2n4celllines AT yunliyu increasedlevelsoffattyacidscontributedtoinductionofhepaticcyp3a4activityinducedbydiabetesinvitroevidencefromhepg2cellandfa2n4celllines AT xintingwang increasedlevelsoffattyacidscontributedtoinductionofhepaticcyp3a4activityinducedbydiabetesinvitroevidencefromhepg2cellandfa2n4celllines AT liliu increasedlevelsoffattyacidscontributedtoinductionofhepaticcyp3a4activityinducedbydiabetesinvitroevidencefromhepg2cellandfa2n4celllines AT xiaodongliu increasedlevelsoffattyacidscontributedtoinductionofhepaticcyp3a4activityinducedbydiabetesinvitroevidencefromhepg2cellandfa2n4celllines
_version_	1725126147620995072

Increased Levels of Fatty Acids Contributed to Induction of Hepatic CYP3A4 Activity Induced by Diabetes — In Vitro Evidence From HepG2 Cell and Fa2N-4 Cell Lines

Similar Items