A critical role for the peroxisome proliferator-activated receptor alpha (PPARalpha) in the cellular fasting response: the PPARalpha-null mouse as a model of fatty acid oxidation disorders.

@article{Leone1999ACR,
  title={A critical role for the peroxisome proliferator-activated receptor alpha (PPARalpha) in the cellular fasting response: the PPARalpha-null mouse as a model of fatty acid oxidation disorders.},
  author={T. Leone and C. Weinheimer and D. Kelly},
  journal={Proceedings of the National Academy of Sciences of the United States of America},
  year={1999},
  volume={96 13},
  pages={
          7473-8
        }
}
We hypothesized that the lipid-activated transcription factor, the peroxisome proliferator-activated receptor alpha (PPARalpha), plays a pivotal role in the cellular metabolic response to fasting. Short-term starvation caused hepatic steatosis, myocardial lipid accumulation, and hypoglycemia, with an inadequate ketogenic response in adult mice lacking PPARalpha (PPARalpha-/-), a phenotype that bears remarkable similarity to that of humans with genetic defects in mitochondrial fatty acid… Expand
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It is demonstrated that the lipid-activated nuclear receptor, peroxisome proliferator-activated receptor α (PPARα), regulates the expression of several key enzymes involved in cardiac mitochondrial FAO, identifying an important role for PPARα in the control of cardiac lipid metabolism. Expand
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It is shown that jerboa (Jaculus orientalis) liver expresses both active wild-type PPAR alpha (PPARalpha1wt) and truncated PPARalpha forms and that the PPAR Alpha1wt to truncatedPPAR alpha2 ratio, which indicates the availability of active PPARAlpha1wt, is differentially regulated during fasting-associated hibernation. Expand
Defect in Peroxisome Proliferator-activated Receptor α-inducible Fatty Acid Oxidation Determines the Severity of Hepatic Steatosis in Response to Fasting*
TLDR
Observations point to the critical importance of PPARα in the transcriptional regulatory responses to fasting and in determining the severity of hepatic steatosis. Expand
Constitutive Regulation of Cardiac Fatty Acid Metabolism through Peroxisome Proliferator-activated Receptor α Associated with Age-dependent Cardiac Toxicity*
TLDR
The results presented here indicate that PPARα controls constitutive fatty acid oxidation, thus establishing a role for the receptor in cardiac fatty acid homeostasis and altered expression of fatty acid-metabolizing proteins seems to lead to myocardial damage and fibrosis. Expand
Peroxisome Proliferator-activated Receptor α (PPARα) Agonist Treatment Reverses PPARα Dysfunction and Abnormalities in Hepatic Lipid Metabolism in Ethanol-fed Mice*
Proper function of the peroxisome proliferator-activated receptor α (PPARα) is essential for the regulation of hepatic fatty acid metabolism. Fatty acid levels are increased in liver during theExpand
Identification of Peroxisome Proliferator-responsive Human Genes by Elevated Expression of the Peroxisome Proliferator-activated Receptor α in HepG2 Cells*
TLDR
The data suggest that humans retain a capacity for PPARα regulation of mitochondrial fatty acid oxidation and ketogenesis, and that human liver is refractory to peroxisome proliferation. Expand
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TLDR
The present findings suggest that downregulation of Pparalpha and its coactivators in tissues with high rates of fatty acid catabolism is responsible for the reduced utilization of fatty acids in liver and skeletal muscle and the reduced thermogenesis occurring in the lactating animal, which aim to conserve energy and metabolic substrates for milk production in the mammary gland. Expand
Peroxisome proliferator-activated receptor alpha mediates the effects of high-fat diet on hepatic gene expression.
TLDR
PPARalpha and PPARalpha-signaling are activated in liver by chronic high-fat feeding; PPARgamma may compensate for PPAR Alpha in PPAR alpha null mice on HFD; and Adenoviral overexpression of PPargamma in liver indicated that PPARGamma can up-regulate genes involved in lipo/adipogenesis but also characteristic PPARAlpha targets involved in fatty acid oxidation. Expand
A Role for Peroxisome Proliferator-activated Receptor α (PPARα) in the Control of Cardiac Malonyl-CoA Levels
TLDR
It is demonstrated that PPARα is an important regulator of fatty acid oxidation in the heart and that this regulation of fatty acids oxidation may in part occur due to the transcriptional control of malonyl-CoA decarboxylase. Expand
Developmental and tissue-specific involvement of peroxisome proliferator-activated receptor-alpha in the control of mouse uncoupling protein-3 gene expression.
TLDR
It is found that peroxisome proliferator-activated receptor-alpha (PPARalpha) on the control of UCP3 gene expression depends on the tissue and developmental stage, and PPARalpha-dependent regulation is required for appropriate gene regulation of U CP3 as part of the subset of fatty-acid-responsive genes in neonatal muscle and heart. Expand
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References

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The role of the peroxisome proliferator-activated receptor α (PPARα) in the control of cardiac lipid metabolism
TLDR
It is demonstrated that the lipid-activated nuclear receptor, peroxisome proliferator-activated receptor α (PPARα), regulates the expression of several key enzymes involved in cardiac mitochondrial FAO, identifying an important role for PPARα in the control of cardiac lipid metabolism. Expand
A gender-related defect in lipid metabolism and glucose homeostasis in peroxisome proliferator- activated receptor alpha- deficient mice.
TLDR
A pivotal role for PPARalpha in lipid and glucose homeostasis in vivo is demonstrated and estrogen signaling pathways in the regulation of cardiac and hepatic lipid metabolism are implicate. Expand
Altered Constitutive Expression of Fatty Acid-metabolizing Enzymes in Mice Lacking the Peroxisome Proliferator-activated Receptor α (PPARα)*
TLDR
PPARα modulates constitutive expression of genes encoding several mitochondrial fatty acid-catabolizing enzymes in addition to mediating inducible mitochondrial and peroxisomal fatty acid β-oxidation, thus establishing a role for the receptor in fatty acid homeostasis. Expand
The peroxisome proliferator-activated receptor regulates mitochondrial fatty acid oxidative enzyme gene expression.
TLDR
Results dictate an expanded role for the PPAR in the regulation of FA metabolism and indicates that intracellular FA metabolites that accumulate during inhibition can regulate MCAD expression and are likely candidates for PPAR ligand(s). Expand
Peroxisome Proliferator-activated Receptor α Controls the Hepatic CYP4A Induction Adaptive Response to Starvation and Diabetes*
TLDR
It is unambiguously demonstrated that PPARα is strictly required for hepatic CYP4A induction by starvation and diabetes, and represents the first evidence for the pathophysiologically induced activation of a nuclear receptor. Expand
Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators
TLDR
It is demonstrated that mPPAR alpha is the major isoform required for mediating the pleiotropic response resulting from the actions of peroxisome proliferators. Expand
Peroxisome Proliferator-activated Receptor α-Isoform Deficiency Leads to Progressive Dyslipidemia with Sexually Dimorphic Obesity and Steatosis*
TLDR
These studies demonstrate the involvement of PPARα nuclear receptor in lipid homeostasis, with a sexually dimorphic control of circulating lipids, fat storage, and obesity in rodents. Expand
Fatty Acids Activate Transcription of the Muscle Carnitine Palmitoyltransferase I Gene in Cardiac Myocytes via the Peroxisome Proliferator-activated Receptor α*
TLDR
It is demonstrated that long-chain fatty acids regulate the transcription of a gene encoding a pivotal enzyme in the mitochondrial fatty acid uptake pathway in cardiac myocytes and define a role for PPARα in the control of myocardial lipid metabolism. Expand
Control of Human Muscle-type Carnitine Palmitoyltransferase I Gene Transcription by Peroxisome Proliferator-activated Receptor*
TLDR
Results show that PPAR regulates the entry of fatty acids into the mitochondria, which is a crucial step in their metabolism, especially in tissues like heart, skeletal muscle and brown adipose tissue in which fatty acids are a major source of energy. Expand
Fatty acids and retinoids control lipid metabolism through activation of peroxisome proliferator-activated receptor-retinoid X receptor heterodimers.
TLDR
The data demonstrate a convergence of the PPAR and RXR signaling pathways in the regulation of the peroxisomal beta-oxidation of fatty acids by fatty acids and retinoids. Expand
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