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

Leone, Teresa C.; Weinheimer, Carla J.; Kelly, Daniel P.

doi:10.1073/pnas.96.13.7473

Cited by 883 publications

(781 citation statements)

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“…During a fast, when increased utilization of free fatty occurs, PPARα expression and activity promotes increased β-oxidation. In fact, while PPARα mice are relatively healthy when fed ad libitum, they have very poor tolerance for fasting and develop hypoglycemia, hypoketonemia and hypothermia (Kersten et al 1999;Leone et al 1999). In skeletal muscle, loss of PPARα is relatively mild, suggesting PPARδ and perhaps other factors may compensate (Muoio et al 2002).…”

Section: Pparmentioning

confidence: 99%

Nuclear receptors, mitochondria and lipid metabolism

2008

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Lipid metabolism is a continuum from emulsification and uptake of lipids in the intestine to cellular uptake and transport to compartments such as mitochondria. Whether fats are shuttled into lipid droplets in adipose tissue or oxidized in mitochondria and peroxisomes depends on metabolic substrate availability, energy balance and endocrine signaling of the organism. Several members of the nuclear hormone receptor superfamily are lipid-sensing factors that affect all aspects of lipid metabolism. The physiologic actions of glandular hormones (e.g. thyroid, mineralocorticoid and glucocorticoid), vitamins (e.g. vitamins A and D) and reproductive hormones (e.g. progesterone, estrogen and testosterone) and their cognate receptors are well established. The peroxisome proliferator activated receptors (PPARs) and Liver X receptors (LXRs), acting in concert with PPARγ Coactivator 1α (PGC-1α), have been shown to regulate insulin sensitivity and lipid handling. These receptors are the focus of intense pharmacologic studies to expand the armamentarium of small molecule ligands to treat diabetes and the metabolic syndrome (hypertension, insulin resistance, hyperglycemia, dyslipidemia, and obesity). Recently, additional partners of PGC-1α have moved to the forefront of metabolic research, the Estrogen-related Receptors (ERRs). Although no endogenous ligands for these receptors have been identified, phenotypic analyses of knockout mouse models demonstrate an important role for these molecules in substrate sensing and handling as well as mitochondrial function.

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Section: Pparmentioning

confidence: 99%

Nuclear receptors, mitochondria and lipid metabolism

2008

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“…5). Since MCAD gene expression is highly dependent on nutritional status (22), the variation in peroxisomal β-oxidation is not likely to be related to nutritional status.…”

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Regulation of the Liver Fatty Acid Binding Protein Gene (L-FABP) by Hepatocyte NuclearFactor 1aplha: alterations in fatty acid homeostasis in HNF1alpha-deficient mice

Akiyama

Ward

Gonzalez

2000

Journal of Biological Chemistry

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“…The expression of enzymes involved in fatty acid ␤-oxidation (FAO), 1 the principal source of energy production in the adult mammalian heart, is tightly controlled at the transcriptional level during cardiac development and in response to physiologic and pathophysiologic stimuli (1-7). The nuclear receptor PPAR␣ has been shown to serve as a key transcriptional regulator of this energy metabolic pathway (Ref.…”

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confidence: 99%

p38 Mitogen-activated Protein Kinase Activates Peroxisome Proliferator-activated Receptor α

Barger

Browning

Garner

et al. 2001

Journal of Biological Chemistry

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243

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The expression of enzymes involved in fatty acid ␤-oxidation (FAO), the principal source of energy production in the adult mammalian heart, is controlled at the transcriptional level via the nuclear receptor peroxisome proliferator-activated receptor ␣ (PPAR␣). Evidence has emerged that PPAR␣ activity is activated as a component of an energy metabolic stress response. The p38 mitogen-activated protein kinase (MAPK) pathway is activated by cellular stressors in the heart, including ischemia, hypoxia, and hypertrophic growth stimuli. We show here that PPAR␣ is phosphorylated in response to stress stimuli in rat neonatal cardiac myocytes; in vitro kinase assays demonstrated that p38 MAPK phosphorylates serine residues located within the NH 2 -terminal A/B domain of the protein. Transient transfection studies in cardiac myocytes and in CV-1 cells utilizing homologous and heterologous PPAR␣ target element reporters and mammalian one-hybrid transcription assays revealed that p38 MAPK phosphorylation of PPAR␣ significantly enhanced ligand-dependent transactivation. Cotransfection studies performed with several known coactivators of PPAR␣ demonstrated that p38 MAPK markedly increased coactivation specifically by PGC-1, a transcriptional coactivator implicated in myocyte energy metabolic gene regulation and mitochondrial biogenesis. These results identify PPAR␣ as a downstream effector of p38 kinase-dependent stress-activated signaling in the heart, linking extracellular stressors to alterations in energy metabolic gene expression.The expression of enzymes involved in fatty acid ␤-oxidation (FAO), 1 the principal source of energy production in the adult mammalian heart, is tightly controlled at the transcriptional level during cardiac development and in response to physiologic and pathophysiologic stimuli (1-7). The nuclear receptor PPAR␣ has been shown to serve as a key transcriptional regulator of this energy metabolic pathway (Ref. 8; reviewed in Ref. 9). PPAR␣ is a member of the nuclear receptor superfamily of transcription factors and binds cognate response elements as an obligate heterodimer with the retinoid X receptor (RXR). PPAR␣ is ligand-activated by a variety of natural and synthetic agonists, including arachidonic acid derivatives, fibrates, and long-chain fatty acids: metabolic substrates for cardiac FAO enzymes. The important role played by PPAR␣ in cardiac metabolism is underscored by the marked reduction in the basal level of cardiac FAO enzyme gene expression in PPAR␣ Ϫ/Ϫ mice (10, 11), leading to reduced long-chain fatty acid uptake and oxidation (12).Evidence has emerged that PPAR␣ plays a critical role in the energy metabolic stress response in tissues that rely largely on mitochondrial fat oxidation for energy production, such as heart and liver. Under normal physiologic conditions, the expression of cardiac FAO enzyme genes are induced after a short term fast coincident with increased use of fatty acids for myocardial energy production (1, 3). In contrast, PPAR␣ Ϫ/Ϫ mice do not exhibit the expecte...

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

Cited by 883 publications

References 45 publications

Nuclear receptors, mitochondria and lipid metabolism

Nuclear receptors, mitochondria and lipid metabolism

Regulation of the Liver Fatty Acid Binding Protein Gene (L-FABP) by Hepatocyte NuclearFactor 1aplha: alterations in fatty acid homeostasis in HNF1alpha-deficient mice

p38 Mitogen-activated Protein Kinase Activates Peroxisome Proliferator-activated Receptor α

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