Regulation of liver carnitine palmitoyltransferase I gene expression by hormones and fatty acids

2001 ◽  
Vol 29 (2) ◽  
pp. 310-316 ◽  
Author(s):  
J.-F. Louet ◽  
C. Le May ◽  
J.-P. Pégorier ◽  
J.-F. Decaux ◽  
J. Girard
Keyword(s):  
Fatty Acids ◽  
Gene Transcription ◽  
Peroxisome Proliferator ◽  
Gene Encoding ◽  
First Intron ◽  
Transcriptional Effect ◽  
Carnitine Palmitoyltransferase I ◽  
Responsive Element ◽  
Cpt I ◽  
I Gene

This brief review focuses on the transcriptional regulation of liver carnitine palmitoyltransferase I (L-CPT I) by pancreatic and thyroid hormones and by long-chain fatty acids (LCFA). Both glucagon and 3,3′,5-tri-iodothyronine (T3) enhanced the transcription of the gene encoding L-CPT I, whereas insulin had the opposite effect. Interestingly, the transcriptional effect of T3 required, in addition to the thyroid-responsive element, the co-operation of a sequence located in the first intron of L-CPT I gene. Non-esterified fatty acids rather than acyl-CoA ester or intramitochondrial metabolite were responsible for the transcriptional effect on the gene encoding LCPT I. It was shown that LCFA and peroxisome proliferators stimulated L-CPT I gene transcription by distinct mechanisms. Peroxisome proliferator stimulated L-CPT I gene transcription through a peroxisome-proliferator-responsive element (PPRE) located at -2846 bp, whereas LCFA induced L-CPT I gene transcription through a peroxisome-proliferator-activated receptor α (PPARα)-independent mechanism owing to a sequence located in the first intron of the gene.

Cyclic AMP and Fatty Acids Increase Carnitine Palmitoyltransferase I Gene Transcription in Cultured Fetal Rat Hepatocytes

1996 ◽  
Vol 235 (3) ◽  
pp. 789-798 ◽  
Author(s):  
Florence Chatelain ◽  
Claude Kohl ◽  
Victoria Esser ◽  
J. Denis Mcgarry ◽  
Jean Girard ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Cyclic Amp ◽  
Gene Transcription ◽  
Rat Hepatocytes ◽  
Carnitine Palmitoyltransferase ◽  
Fetal Rat ◽  
Carnitine Palmitoyltransferase I ◽  
I Gene

Long-chain fatty acids regulate liver carnitine palmitoyltransferase I gene (L-CPT I) expression through a peroxisome-proliferator-activated receptor α (PPARα)-independent pathway

2001 ◽  
Vol 354 (1) ◽  
pp. 189-197 ◽  
Author(s):  
Jean-Francç;ois LOUET ◽  
Florence CHATELAIN ◽  
Jean-Francç;ois DECAUX ◽  
Edwards A. PARK ◽  
Claude KOHL ◽  
...  
Keyword(s):  
Gene Expression ◽  
Carnitine Palmitoyltransferase ◽  
Dietary Lipids ◽  
Lipid Lowering ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Carnitine Palmitoyltransferase I ◽  
Cpt I ◽  
I Gene ◽  
Long Chain

Liver carnitine palmitoyltransferase I (L-CPT I) catalyses the transfer of long-chain fatty acid (LCFA) for translocation across the mitochondrial membrane. Expression of the L-CPT I gene is induced by LCFAs as well as by lipid-lowering compounds such as clofibrate. Previous studies have suggested that the peroxisome-proliferator-activated receptor α (PPARα) is a common mediator of the transcriptional effects of LCFA and clofibrate. We found that free LCFAs rather than acyl-CoA esters are the signal metabolites responsible for the stimulation of L-CPT I gene expression. Using primary culture of hepatocytes we found that LCFAs failed to stimulate L-CPT I gene expression both in wild-type and PPARα-null mice. These results suggest that the PPARα-knockout mouse does not represent a suitable model for the regulation of L-CPT I gene expression by LCFAs in the liver. Finally, we determined that clofibrate stimulates L-CPT I through a classical direct repeat 1 (DR1) motif in the promoter of the L-CPT I gene while LCFAs induce L-CPT I via elements in the first intron of the gene. Our results demonstrate that LCFAs can regulate gene expression through PPARα-independent pathways and suggest that the regulation of gene expression by dietary lipids is more complex than previously proposed.

scholarly journals Cloning and characterization of the promoter for the liver isoform of the rat carnitine palmitoyltransferase I (L-CPT I) gene

1998 ◽  
Vol 330 (1) ◽  
pp. 217-224 ◽  
Author(s):  
A. Edwards PARK ◽  
L. Michelle STEFFEN ◽  
Shulan SONG ◽  
M. Vicki PARK ◽  
A. George COOK
Keyword(s):  
Genomic Library ◽  
Transcriptional Start Site ◽  
Carnitine Palmitoyltransferase ◽  
Proximal Promoter ◽  
Exon 2 ◽  
Exon 1 ◽  
Carnitine Palmitoyltransferase I ◽  
Specific Regulation ◽  
Cpt I ◽  
I Gene

Carnitine palmitoyltransferase I (CPT I) catalyses the transfer of long chain fatty acids to carnitine for translocation across the mitochondrial inner membrane. The cDNAs of two isoforms of CPT I, termed the hepatic and muscle isoforms, have been cloned. Expression of the hepatic CPT I gene (L-CPT I) is subject to developmental, hormonal and tissue specific regulation. We have cloned the promoter of the L-CPT I gene from a rat genomic library. In the L-CPT I gene, there are two exons 5ʹ to the exon containing the ATG that initiates translation. Exon 1 and the 5ʹ end of exon 2 contain sequences that were not previously described in the rat L-CPT I cDNA. There is an alternatively spliced form of the L-CPT I mRNA in which exon 2 is skipped. The proximal promoter of the L-CPT I gene is extremely GC rich and does not contain a TATA box. There are several putative Sp1 binding sites near the transcriptional start site. A 190 base pair fragment of the promoter can efficiently drive transcription of luciferase and CAT (chloramphenicol acetyltransferase) reporter genes transiently transfected into HepG2 cells. Sequences in both the first intron and the promoter contribute to basal expression. Our results provide the foundation for further studies into the regulation of L-CPTI gene expression.

scholarly journals Adenovirus-mediated overexpression of liver carnitine palmitoyltransferase I in INS1E cells: effects on cell metabolism and insulin secretion

2002 ◽  
Vol 364 (1) ◽  
pp. 219-226 ◽  
Author(s):  
Blanca RUBÍ ◽  
Peter A. ANTINOZZI ◽  
Laura HERRERO ◽  
Hisamitsu ISHIHARA ◽  
Guillermina ASINS ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Insulin Secretion ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Fold Increase ◽  
Acid Oxidation ◽  
Β Cells ◽  
Β Cell ◽  
Carnitine Palmitoyltransferase I ◽  
Cpt I

Lipid metabolism in the β-cell is critical for the regulation of insulin secretion. Pancreatic β-cells chronically exposed to fatty acids show higher carnitine palmitoyltransferase I (CPT I) protein levels, higher palmitate oxidation rates and an altered insulin response to glucose. We examined the effect of increasing CPT I levels on insulin secretion in cultured β-cells. We prepared a recombinant adenovirus containing the cDNA for the rat liver isoform of CPT I. The overexpression of CPT I in INS1E cells caused a more than a 5-fold increase in the levels of CPT I protein (detected by Western blotting), a 6-fold increase in the CPT activity, and an increase in fatty acid oxidation at 2.5mM glucose (1.7-fold) and 15mM glucose (3.1-fold). Insulin secretion was stimulated in control cells by 15mM glucose or 30mM KCl. INS1E cells overexpressing CPT I showed lower insulin secretion on stimulation with 15mM glucose (−40%; P<0.05). This decrease depended on CPT I activity, since the presence of etomoxir, a specific inhibitor of CPT I, in the preincubation medium normalized the CPT I activity, the fatty-acid oxidation rate and the insulin secretion in response to glucose. Exogenous palmitate (0.25mM) rescued glucose-stimulated insulin secretion (GSIS) in CPT I-overexpressing cells, indicating that the mechanism of impaired GSIS was through the depletion of a critical lipid. Depolarizing the cells with KCl or intermediary glucose concentrations (7.5mM) elicited similar insulin secretion in control cells and cells overexpressing CPT I. Glucose-induced ATP increase, glucose metabolism and the triacylglycerol content remained unchanged. These results provide further evidence that CPT I activity regulates insulin secretion in the β-cell. They also indicate that up-regulation of CPT I contributes to the loss of response to high glucose in β-cells exposed to fatty acids.

Differential Regulation of Carnitine Palmitoyltransferase-I Gene Isoforms (CPT-I α and CPT-Iβ ) in the Rat Heart

2001 ◽  
Vol 33 (2) ◽  
pp. 317-329 ◽  
Author(s):  
George A. Cook ◽  
Timmye L. Edwards ◽  
Michelle S. Jansen ◽  
Suleiman W. Bahouth ◽  
Henry G. Wilcox ◽  
...  
Keyword(s):  
Rat Heart ◽  
Differential Regulation ◽  
Carnitine Palmitoyltransferase ◽  
Carnitine Palmitoyltransferase I ◽  
Gene Isoforms ◽  
Cpt I ◽  
I Gene

scholarly journals Functional analysis of peroxisome-proliferator-responsive element motifs in genes of fatty acid-binding proteins

2004 ◽  
Vol 382 (1) ◽  
pp. 239-245 ◽  
Author(s):  
Christian SCHACHTRUP ◽  
Tanja EMMLER ◽  
Bertram BLECK ◽  
Anton SANDQVIST ◽  
Friedrich SPENER
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Binding Proteins ◽  
Lipid Binding ◽  
Fatty Acid Binding Proteins ◽  
Computer Search ◽  
Peroxisome Proliferator ◽  
Fatty Acid Binding ◽  
Responsive Element

Retinoic acids and long-chain fatty acids are lipophilic agonists of nuclear receptors such as RXRs (retinoic X receptors) and PPARs (peroxisome-proliferator-activated receptors) respectively. These agonists are also ligands of intracellular lipid-binding proteins, which include FABPs (fatty acid-binding proteins). We reported previously that L (liver-type)-FABP targets fatty acids to the nucleus of hepatocytes and affects PPARα activation, which binds together with an RXR subtype to a PPRE (peroxisome-proliferator-responsive element). In the present study, we first determined the optimal combination of murine PPAR/RXR subtypes for binding to known murine FABP-PPREs and to those found by computer search and then tested their in vitro functionality. We show that all PPARs bind to L-FABP-PPRE, PPARα, PPARγ1 and PPARγ2 to A (adipocyte-type)-FABP-PPRE. All PPAR/RXR heterodimers transactivate L-FABP-PPRE, best are combinations of PPARα with RXRα or RXRγ. In contrast, PPARα heterodimers do not transactivate A-FABP-PPRE, best combinations are of PPARγ1 with RXRα and RXRγ, and of PPARγ2 with all RXR subtypes. We found that the predicted E (epidermal-type)- and H (heart-type)-FABP-PPREs are not activated by any PPAR/RXR combination without or with the PPAR pan-agonist bezafibrate. In the same way, C2C12 myoblasts transfected with promoter fragments of E-FABP and H-FABP genes containing putative PPREs are also not activated through stimulation of PPARs with bezafibrate applied to the cells. These results demonstrate that only PPREs of L- and A-FABP promoters are functional, and that binding of PPAR/RXR heterodimers to a PPRE in vitro does not necessarily predict transactivation.

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