Comprehensive analysis of gene expression in rat and human hepatoma cells exposed to the peroxisome proliferator WY14,643

Heuvel, John P. Vanden; Kreder, Dirk; Belda, Benjamin J.; Hannon, Daniel B.; Nugent, Courtney A; Burns, Katherine A.; Taylor, Michael J.

doi:10.1016/s0041-008x(03)00015-2

Cited by 44 publications

(35 citation statements)

References 83 publications

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“…Here we find that incubation with PPAR␣ agonists results in a reduced AQP9 abundance in both rat WIF-B9 and human HepG2 hepatocytes. The effect of PPAR␣ activation on AQP9 protein abundance was less pronounced in the human cell line, which is in line with a previous notion that PPAR␣ activation has a more limited effect in HepG2 hepatocytes compared with a rat hepatoma cell line (36). Our results are in contrast to a previous study using HepG2 hepatocytes in which WY 14643 caused a marked increase in AQP9 abundance (18).…”

Section: Discussionsupporting

confidence: 87%

Hepatic AQP9 expression in male rats is reduced in response to PPARα agonist treatment

Lebeck

Cheema

Skowroński

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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Lebeck J, Cheema MU, Skowronski MT, Nielsen S, Praetorius J. Hepatic AQP9 expression in male rats is reduced in response to PPAR␣ agonist treatment. Am J Physiol Gastrointest Liver Physiol 308: G198 -G205, 2015. First published December 4, 2014 doi:10.1152/ajpgi.00407.2013.-The peroxisome proliferator receptor ␣ (PPAR␣) is a key regulator of the hepatic response to fasting with effects on both lipid and carbohydrate metabolism. A role in hepatic glycerol metabolism has also been found; however, the results are somewhat contradictive. Aquaporin 9 (AQP9) is a pore-forming transmembrane protein that facilitates hepatic uptake of glycerol. Its expression is inversely regulated by insulin in male rodents, with increased expression during fasting. Previous results indicate that PPAR␣ plays a crucial role in the induction of AQP9 mRNA during fasting. In the present study, we use PPAR␣ agonists to explore the effect of PPAR␣ activation on hepatic AQP9 expression and on the abundance of enzymes involved in glycerol metabolism using both in vivo and in vitro systems. In male rats with free access to food, treatment with the PPAR␣ agonist WY 14643 (3 mg·kg Ϫ1 ·day Ϫ1 ) caused a 50% reduction in hepatic AQP9 abundance with the effect being restricted to AQP9 expressed in periportal hepatocytes. The pharmacological activation of PPAR␣ had no effect on the abundance of GlyK, whereas it caused an increased expression of hepatic GPD1, GPAT1, and L-FABP protein. In WIF-B9 and HepG2 hepatocytes, both WY 14643 and another PPAR␣ agonist GW 7647 reduced the abundance of AQP9 protein. In conclusion, pharmacological PPAR␣ activation results in a marked reduction in the abundance of AQP9 in periportal hepatocytes. Together with the effect on the enzymatic apparatus for glycerol metabolism, our results suggest that PPAR␣ activation in the fed state directs glycerol into glycerolipid synthesis rather than into de novo synthesis of glucose. aquaporin-9; immunohistochemistry; WY 14643; hepatocytes; glycerol metabolism PEROXISOME PROLIFERATOR RECEPTOR ␣ (PPAR␣) is a ligandactivated transcription factor that belongs to the superfamily of nuclear hormone receptors (39). After binding of ligands such as free fatty acids and fibrates, PPAR␣ and its coactivators influence the transcription of target genes either by binding to response elements in the corresponding promoter region (PPREs) or by interfering with other transcription factors (39). Fibrates are used in the treatment of hypertriglyceridemia and PPAR␣ regulates the expression of several proteins involved in lipid metabolism that promotes the removal of triglycerides (TG) from the circulation and enhances ␤-oxidation and ketogenesis in the liver (11). The induction of these pathways is particularly vital during starvation and PPAR␣ knockout (KO) mice respond to fasting with hypoketonemia, hypothermia, and hypoglycemia (12). Several mechanisms have been proposed to explain the fasting-induced hypoglycemia, including decreased hepatic glucose production (12, 21) as well as increased extr...

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Section: Discussionsupporting

confidence: 87%

Hepatic AQP9 expression in male rats is reduced in response to PPARα agonist treatment

Lebeck

Cheema

Skowroński

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…The insulin-induced transactivation is due to the phosphorylation of two serines (12 and 21) in the A/B domain of human PPARα [28]. Co-transfection of MAPK phosphatase-1 (MKP-1) with PPARα resulted in a decrease in ligand inducible reporter activity [29], once again enforcing the role of the MAPK pathway on this NR. Interestingly, although the phosphorylation is in the A/B domain of PPARα, there is an effect on the ligand-dependent transactivation and not the ligand-independent AF-1 domain.…”

Section: Extracellular Receptor Kinase-mitogen Activated Protein Kinamentioning

confidence: 94%

Modulation of PPAR activity via phosphorylation

Burns

Heuvel

2007

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

390

327

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Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily of transcription factors that respond to specific ligands by altering gene expression in a cell-, developmental-and sex-specific manner. Three subtypes of this receptor have been discovered (PPARα, β and γ), each apparently evolving to fulfill different biological niches. PPARs control a variety of target genes involved in lipid homeostasis, diabetes and cancer. Similar to other nuclear receptors, the PPARs are phosphoproteins and their transcriptional activity is affected by cross-talk with kinases and phosphatases. Phosphorylation by the mitogen-activated protein kinases (ERK-and p38-MAPK), Protein Kinase A and C (PKA, PKC), AMP Kinase (AMPK) and glycogen synthase kinase-3 (GSK3) affect their activity in a ligand-dependent or -independent manner. The effects of phosphorylation depend on the cellular context, receptor subtype and residue metabolized which can be manifested at several steps in the PPAR activation sequence including ligand affinity, DNA binding, coactivator recruitment and proteasomal degradation. The review will summarize the known PPAR kinases that directly act on these receptors, the sites affected and the result of this modification on receptor activity.

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“….html regulated by PPAR ␣ . Previous studies showed that Wy14,643, an activator of PPAR ␣ , upregulated expression of liver fatty acid-binding protein ( Fabp1 ), enoyl-CoA hydratase/3-hydroxyacyl CoA dehydrogenase ( Ehhadh ), cytochrome P450 CYP4A enzyme ( Cyp4a1 ) and carnitine palmitoyltransferase ( Cpt1a , Cpt2 ) in mouse liver cells ( 10 ) and in the rat hepatoma cell line, FaO ( 33 ). We cultured FaO cells with EPA, 8-HEPE, or GW7647, a PPAR ␣ -specifi c agonist, for 6 h. Expression of Fabp1 , Ehhadh , and Cpt1a was increased by 8-HEPE, but not by EPA; expression of Cyp4a1 and Cpt2 was increased by EPA and 8-HEPE.…”

Section: Activation Of Transcription Of Gal4-ppars By Pacifi C Krill mentioning

confidence: 99%

Hydroxyeicosapentaenoic acids from the Pacific krill show high ligand activities for PPARs

Yamada

Oshiro

Kikuchi

et al. 2014

Journal of Lipid Research

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Comprehensive analysis of gene expression in rat and human hepatoma cells exposed to the peroxisome proliferator WY14,643

Cited by 44 publications

References 83 publications

Hepatic AQP9 expression in male rats is reduced in response to PPARα agonist treatment

Hepatic AQP9 expression in male rats is reduced in response to PPARα agonist treatment

Modulation of PPAR activity via phosphorylation

Hydroxyeicosapentaenoic acids from the Pacific krill show high ligand activities for PPARs

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