Gene Expression Changes Induced by PPAR Gamma Agonists in Animal and Human Liver

Rogue, Alexandra; Spire, Catherine; Brun, Marion; Claude, Nancy; Guillouzo, André

doi:10.1155/2010/325183

Cited by 104 publications

(81 citation statements)

References 90 publications

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“…Rosiglitazone is a known mild PXR inducer (Sinz et al, 2006); however, if rosiglitazone was operating through the PXR receptor, then rifampin should have induced mRNA as well. Rosiglitazone is potentially binding and inducing CYP2J2 through peroxisome proliferator-activated receptor (PPAR), which also induces mRNA of CYP2B and CYP4 enzymes (Rogue et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Activity, Inhibition, and Induction of Cytochrome P450 2J2 in Adult Human Primary Cardiomyocytes

et al. 2013

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Cytochrome P450 2J2 plays a significant role in the epoxidation of arachidonic acid to signaling molecules important in cardiovascular events. CYP2J2 also contributes to drug metabolism and is responsible for the intestinal clearance of ebastine. However, the interaction between arachidonic acid metabolism and drug metabolism in cardiac tissue, the main expression site of CYP2J2, has not been examined. Here we investigate an adult-derived human primary cardiac cell line as a suitable model to study metabolic drug interactions (inhibition and induction) of CYP2J2 in cardiac tissue. The primary human cardiomyocyte cell line demonstrated similar mRNA-expression profiles of P450 enzymes to adult human ventricular tissue. CYP2J2 was the dominant isozyme with minor contributions from CYP2D6 and CYP2E1. Both terfenadine and astemizole oxidation were observed in this cell line, whereas midazolam was not metabolized suggesting lack of CYP3A activity. Compared with recombinant CYP2J2, terfenadine was hydroxylated in cardiomyocytes at a similar K m value of 1.5 mM. The V max of terfenadine hydroxylation in recombinant enzyme was found to be 29.4 pmol/pmol P450 per minute and in the cells 6.0 pmol/pmol P450 per minute. CYP2J2 activity in the cell line was inhibited by danazol, astemizole, and ketoconazole in submicromolar range, but also by xenobiotics known to cause cardiac adverse effects. Of the 14 compounds tested for CYP2J2 induction, only rosiglitazone increased mRNA expression, by 1.8-fold. This cell model can be a useful in vitro model to investigate the role of CYP2J2-mediated drug metabolism, arachidonic acid metabolism, and their association to drug induced cardiotoxicity.

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Section: Discussionmentioning

confidence: 99%

Activity, Inhibition, and Induction of Cytochrome P450 2J2 in Adult Human Primary Cardiomyocytes

et al. 2013

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“…For native SW872, vector control, and CETP + cells, the expression of these transcription factor genes followed the same order: CEBP ␤ > PPAR ␥ > CEBP ␣ . The expression of SREBF1 , a master regulator of lipid synthesis, was unchanged, and the expression of PPAR ␥ target genes such as PNPLA2 , FASN , and APOE ( 28,29 ) was not different in CETP + cells ( Table 2 ). SCL2A4 and FABP4 levels were reduced by about half.…”

Section: Perilipin Western Blotsmentioning

confidence: 99%

Overexpression of full-length cholesteryl ester transfer protein in SW872 cells reduces lipid accumulation

Izem

Greene

Białkowska

et al. 2015

Journal of Lipid Research

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CETP is also present inside cells where two isoforms exist: full-length CETP, which is equivalent to plasma CETP, and exon 9-deleted CETP, a smaller form derived from alternatively spliced mRNA ( 6 ). The function of exon 9-deleted CETP is poorly understood. Overexpression studies suggest that exon 9-deleted CETP may bind to full-length CETP and hinder its secretion ( 6, 7 ), although this role was not supported by subsequent transgenic mouse studies ( 8 ).Multiple studies suggest that intracellular CETP modulates lipid metabolism. Cell-associated CETP promotes CE uptake from HDL, stimulates the cell's ability to effl ux cholesterol, and infl uences the storage of CE in cells ( 9-12 ). Acute suppression of CETP biosynthesis by antisense oligonucleotides in SW872 cells reduces cholesterol synthesis and increases CE accumulation ( 13 ). SW872 cells chronically defi cient in CETP manifest more profound alterations in lipid metabolism including reduced capacity to store TG ( 14 ). A role for CETP in cellular lipid storage is further supported by observations in transgenic mice. Adipose tissue-specifi c expression of human CETP in mice results in smaller adipocytes containing less TG and cholesterol and signifi cantly reduces the expression of key lipogenic genes ( 15 ). In hypertriglyceridemic mice, CETP expression normalizes subcutaneous adipose depots and visceral adipocyte size ( 16 ). And in humans, a CETP gene variant that affects the coding sequence of both full-length and exon 9-deleted CETP is associated with increased adiposity following long-term overfeeding ( 17 ).Our initial studies in intracellular CETP, which used a molecular approach that reduced both full-length and exon 9-deleted CETP expression, identifi ed multiple aberrations in lipid metabolism and storage ( 13,14 ). In that Abstract Cells produce two cholesteryl ester transfer protein (CETP) isoforms, full-length and a shorter variant produced by alternative splicing. Blocking synthesis of both isoforms disrupts lipid metabolism and storage. To further defi ne the role of CETP in cellular lipid metabolism, we stably overexpressed full-length CETP in SW872 cells. These CETP + cells had several-fold higher intracellular CETP and accumulated 50% less TG due to a 26% decrease in TG synthesis and 2.5-fold higher TG turnover rate. Reduced TG synthesis was due to decreased fatty acid uptake and impaired conversion of diglyceride to TG even though diacylglycerol acyltransferase activity was normal. Sterol-regulatory element binding protein 1 mRNA levels were normal, and although PPAR ␥ expression was reduced, the expression of several of its target genes including adipocyte triglyceride lipase, FASN , and APOE was normal. In cells, multiple proteins transport phospholipids, sterols, and fatty acids between organelles ( 1, 2 ). However, little is known about the molecular mechanisms of cholesteryl ester (CE) and TG transport. A candidate protein for this function is cholesteryl ester transfer protein (CETP). CETP's role in CE and TG transport in plasma ...

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“…Also, TZDs which are strong insulin sensitizers' drugs, act via PPARγ agonism [13,14]. Besides TZDs ben ficial effects in diabetes there are some deteriorating effects following TZDs administration which include hepatotoxicity and hepatic failure [25]. Our results showed that PPARγ gene expression eleva ted by L-carnitine supplementation in diabetic rats, therefore L-carnitine exerts insulin-sensitizing effects by upregulation of PPARγ.…”

Section: T a B L E 2 Body Weight Glucose Insulin And Adiponectin mentioning

confidence: 56%

Effect of L-carnitine administration on serum insulin and adiponectin levels, and AMPK, APPL1 and PPAR? gene expression in STZ-induced diabetic rat liver

Shahouzehi¹,

Barkhordari²,

Aminizadeh³

et al. 2017

Ukr.Biochem.J.

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Gene Expression Changes Induced by PPAR Gamma Agonists in Animal and Human Liver

Cited by 104 publications

References 90 publications

Activity, Inhibition, and Induction of Cytochrome P450 2J2 in Adult Human Primary Cardiomyocytes

Activity, Inhibition, and Induction of Cytochrome P450 2J2 in Adult Human Primary Cardiomyocytes

Overexpression of full-length cholesteryl ester transfer protein in SW872 cells reduces lipid accumulation

Effect of L-carnitine administration on serum insulin and adiponectin levels, and AMPK, APPL1 and PPAR? gene expression in STZ-induced diabetic rat liver

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