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 Human Lupus Plasma Pro-Atherogenic Effects on Cultured Macrophages Are Not Mitigated by Statin Therapy: A Mechanistic LAPS Substudy

Medicina ◽  
2019 ◽  
Vol 55 (9) ◽  
pp. 514 ◽  
Author(s):  
Reiss ◽  
Arain ◽  
Kasselman ◽  
Renna ◽  
Zhen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lupus Erythematosus ◽  
Cholesterol Metabolism ◽  
Lipid Lowering ◽  
Cholesterol Transport ◽  
Atp Binding ◽  
Peroxisome Proliferator ◽  
Atherosclerotic Cardiovascular Disease ◽  
Peroxisome Proliferator Activated Receptor ◽  
Atp Binding Cassette

Background and Objectives: Atherosclerotic cardiovascular disease (CVD) remains a major cause of morbidity and mortality in persons with systemic lupus erythematosus (SLE, lupus). Atherosclerosis, which involves interplay between cholesterol metabolism and cellular inflammatory pathways, is primarily treated with statins since statins have lipid-lowering and anti-inflammatory properties. The Lupus Atherosclerosis Prevention Study (LAPS) was designed to investigate the efficacy of statins against CVD in SLE patients. LAPS demonstrated that 2 years of atorvastatin administration did not reduce atherosclerosis progression in lupus patients. In this LAPs substudy, we use cultured macrophages to explore the atherogenic properties of plasma from LAPS subjects to explain the mechanistic rationale for the inability of statins to reduce CVD in lupus. Materials and Methods: THP-1 differentiated macrophages were treated for 18 h with 10% SLE patient plasma obtained pre- and post-atorvastatin therapy or placebo. Gene expression of the following cholesterol transport genes was measured by qRT-PCR. For efflux—ATP binding cassette transporter (ABC)A1 and ABCG1, 27-hydroxylase, peroxisome proliferator-activated receptor (PPAR)γ, and liver X receptor (LXR)α; and for influx—cluster of differentiation 36 (CD36) and scavenger receptor (ScR)A1. Results: Macrophages exposed to plasma from both statin-treated and placebo-treated groups showed a significant decrease in cholesterol efflux proteins ATP binding cassette (ABC) transporters A1 and ABCG1, an increase in 27-hydroxylase, an increase in the LDL receptor and a decrease in intracellular free cholesterol. No change in influx receptors ScRA1 and CD36, nor nuclear proteins LXRα and PPARγ was observed. Conclusions: Statins do not normalize pro-atherogenic changes induced by lupus and these changes continue to worsen over time. This study provides mechanistic insight into LAPS findings by demonstrating that statins are overall ineffective in altering the balance of cholesterol transport gene expression in human macrophages. Furthermore, our study suggests that statins as a CVD treatment may not be useful in attenuating lipid overload in the SLE environment.

Cold acclimation increases carnitine palmitoyltransferase I activity in oxidative muscle of striped bass

1994 ◽  
Vol 266 (2) ◽  
pp. R405-R412 ◽  
Author(s):  
K. J. Rodnick ◽  
B. D. Sidell
Keyword(s):  
Cold Acclimation ◽  
Striped Bass ◽  
Fatty Acyl ◽  
Thermal Acclimation ◽  
Carnitine Palmitoyltransferase ◽  
Malonyl Coa ◽  
Red Muscle ◽  
Carnitine Palmitoyltransferase I ◽  
Cpt I ◽  
Long Chain

The effect of thermal acclimation on the activity of carnitine palmitoyltransferase I (CPT I), the rate-limiting enzyme for beta-oxidation of long-chain fatty acids, was determined in oxidative red muscle of striped bass (Morone saxatilis) acclimated at 5 or 25 degrees C. As observed in mammalian tissues, malonyl-CoA potently inhibited CPT I activity of mitochondria. Inhibition by malonyl-CoA required inclusions of both bovine serum albumin (BSA) and palmitoyl-CoA in the reaction media. Because BSA binds long-chain fatty acyl-CoAs, this observation suggests that free fatty acyl-CoAs may disrupt mitochondrial membranes and affect the CPT I protein. Cold acclimation increased citrate synthase activity 1.6-fold and total CPT activity 2-fold in homogenates of red muscle; free carnitine increased 62%, and specific activity of CPT I in mitochondria increased 2-fold. No differences were observed between cold- and warm-acclimated fish in substrate-binding properties of CPT I at an assay temperature of 15 degrees C, as judged by the Michaelis constant (Km) for carnitine (0.11 +/- 0.02 vs. 0.13 +/- 0.02 mM) or inhibition of CPT I, as determined by the half-maximal inhibition concentration (IC50) for malonyl-CoA (0.14 +/- 0.05 vs. 0.09 +/- 0.03 microM). Thermal sensitivity of CPT I (Q10 = 2.91 +/- 0.12 vs. 3.02 +/- 0.20) and preference of CPT I for different long-chain fatty acyl-CoA substrates (16:1-CoA = 16:0-CoA > 18:1-CoA) were not altered by thermal acclimation.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Myocardial carnitine palmitoyltransferase I expression and long-chain fatty acid oxidation in fetal and newborn lambs

2004 ◽  
Vol 286 (6) ◽  
pp. H2243-H2248 ◽  
Author(s):  
Beatrijs Bartelds ◽  
Janny Takens ◽  
Gioia B. Smid ◽  
Victor A. Zammit ◽  
Carina Prip-Buus ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Left Ventricular ◽  
Chain Fatty Acid ◽  
Carnitine Palmitoyltransferase ◽  
Long Chain Fatty Acid ◽  
Carnitine Palmitoyltransferase I ◽  
Cpt I ◽  
Long Chain

Carnitine palmitoyltransferase I (CPT I) catalyzes the conversion of acyl-CoA to acylcarnitine at the outer mitochondrial membrane and is a key enzyme in the control of long-chain fatty acid (LC-FA) oxidation. Because myocardial LC-FA oxidation increases dramatically after birth, we determined the extent to which CPT I expression contributes to these changes in the perinatal lamb. We measured the steady-state level of transcripts of the CPT1A and CPT1B genes, which encode the liver (L-CPT I) and muscle CPT I (M-CPT I) isoforms, respectively, as well as the amount of these proteins, their total activity, and the amount of carnitine in left ventricular tissue from fetal and newborn lambs. We compared these data with previously obtained myocardial FA oxidation rates in vivo in the same model. The results showed that CPT1B was already expressed before birth and that total CPT I expression transiently increased after birth. The protein level of M-CPT I was high throughout development, whereas that of L-CPT I was only transiently upregulated in the first week after birth. The total CPT I activity in vitro also increased after birth. However, the increase in myocardial FA oxidation measured in vivo (112-fold) by far exceeded the increase in gene expression (2.2-fold), protein amount (1.1-fold), and enzyme activity (1.2-fold) in vitro. In conclusion, these results stress the importance of substrate supply per se in the postnatal increase in myocardial FA oxidation. M-CPT I is expressed throughout perinatal development, making it a primary target for metabolic modulation of myocardial FA oxidation.

Lipid metabolism and resistin gene expression in insulin-resistant Fischer 344 rats

2002 ◽  
Vol 282 (3) ◽  
pp. E626-E633 ◽  
Author(s):  
James R. Levy ◽  
Byrd Davenport ◽  
John N. Clore ◽  
Wayne Stevens
Keyword(s):  
Gene Expression ◽  
Leptin Resistance ◽  
Peroxisome Proliferator ◽  
Sprague Dawley ◽  
Peroxisome Proliferator Activated Receptor ◽  
Insulin Resistant ◽  
Fischer 344 ◽  
Carnitine Palmitoyltransferase I ◽  
Acyl Coa Oxidase ◽  
F344 Rats

The interrelationship between insulin and leptin resistance in young Fischer 344 (F344) rats was studied. Young F344 and Sprague-Dawley (SD) rats were fed regular chow. F344 animals had two- to threefold higher insulin and triglyceride concentrations and increased stores of triglycerides within liver and muscle. F344 animals gained more body fat. Both acyl-CoA oxidase (ACO) and carnitine palmitoyltransferase I gene expression were 20–50% less in F344 animals than in age-matched SD animals. Peroxisome proliferator-activated receptor-α gene expression was reduced in 70-day-old F344 animals. Finally, resistin gene expression was similar in 70-day-old SD and F344 animals. Resistin gene expression increased fivefold in F344 animals and twofold in SD animals from 70 to 130 days, without a change in insulin sensitivity. We conclude that young F344 animals have both insulin and leptin resistance, which may lead to diminished fatty oxidation and accumulation of triglycerides in insulin-sensitive target tissues. We did not detect a role for resistin in the etiology of insulin resistance in F344 animals.

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