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Protection from Metabolic Dysregulation, Obesity, and Atherosclerosis by Citrus Flavonoids: Activation of Hepatic PGC1α-Mediated Fatty Acid Oxidation.

Mulvihill EE, Huff MW - PPAR Res (2012)

Bottom Line: Studies in a multitude of models including cell culture, animal and clinical studies demonstrate that citrus-derived flavonoids have therapeutic potential to attenuate dyslipidemia, correct hyperinsulinemia and hyperglycemia, and reduce atherosclerosis.Emerging evidence suggests the metabolic regulators, PPARα and PGC1α, are targets of the citrus flavonoids, and their activation may be at least partially responsible for mediating their metabolic effects.Molecular studies will add significantly to the concept of these flavonoids as viable and promising therapeutic agents to treat the dysregulation of lipid homeostasis, metabolic disease, and its cardiovascular complications.

View Article: PubMed Central - PubMed

Affiliation: Vascular Biology Group, Robarts Research Institute, 100 Perth Drive, London, ON, Canada N6A 5K8.

ABSTRACT
Studies in a multitude of models including cell culture, animal and clinical studies demonstrate that citrus-derived flavonoids have therapeutic potential to attenuate dyslipidemia, correct hyperinsulinemia and hyperglycemia, and reduce atherosclerosis. Emerging evidence suggests the metabolic regulators, PPARα and PGC1α, are targets of the citrus flavonoids, and their activation may be at least partially responsible for mediating their metabolic effects. Molecular studies will add significantly to the concept of these flavonoids as viable and promising therapeutic agents to treat the dysregulation of lipid homeostasis, metabolic disease, and its cardiovascular complications.

No MeSH data available.


Related in: MedlinePlus

Regulation of gene expression by peroxisome proliferator-activated receptors. The nuclear hormone receptor PPARα induces transcription through formation of a heterodimer with the retinoic X receptor and binding to peroxisome proliferator response elements (most are direct repeats with one intervening nucleotide) in the promoter of genes involved in fatty acid oxidation. PGC1α is an important PPARα coactivator in tissues that undergo extensive oxidative metabolism and induce mitochondrial expansion.
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Related In: Results  -  Collection


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fig1: Regulation of gene expression by peroxisome proliferator-activated receptors. The nuclear hormone receptor PPARα induces transcription through formation of a heterodimer with the retinoic X receptor and binding to peroxisome proliferator response elements (most are direct repeats with one intervening nucleotide) in the promoter of genes involved in fatty acid oxidation. PGC1α is an important PPARα coactivator in tissues that undergo extensive oxidative metabolism and induce mitochondrial expansion.

Mentions: Peroxisome proliferator-activated receptor alpha (PPARα) is a member of the family of nuclear hormone receptors which function as ligand activated transcription factors, with a signature type II zinc finger DNA binding motif, to control the expression of specific genes involved in fatty acid utilization [19, 20] (Figure 1). Liver, muscle, kidney, and brown adipose tissue express high levels of PPARα [20, 21]. The endogenous ligands for PPARα activation include fatty acids and their metabolites [22]. PPARs control expression of genes by partnering with RXR and binding to peroxisome proliferator response elements (PPREs) in the promoter of target genes, ultimately resulting in the stimulation of FA oxidation. In mice, receptor agonists cause proliferation of peroxisomes which serve to oxidize long chain fatty acids and detoxify xenobiotic compounds [23]. PPARα is an activator of genes involved in β-oxidation including carnitine palmitoyl transferase 1 (CPT1α) and acyl-CoA oxidase (ACOX). In the liver, fatty acid oxidation is primarily regulated by the level of CPT1 [24]. CPT1α expression is controlled by a complex of transcription factors including PPARγ-coactivator 1 α (PGC1α) and PPARα [24]. CPT1 is found on the outer surface of the mitochondria and transports fatty acids into the mitochondria by the formation of an acyl-carnitine molecule. Upon entry into the inner side of the mitochondrial membrane, CPT2 removes the carnitine, reforming acyl-CoA [24].


Protection from Metabolic Dysregulation, Obesity, and Atherosclerosis by Citrus Flavonoids: Activation of Hepatic PGC1α-Mediated Fatty Acid Oxidation.

Mulvihill EE, Huff MW - PPAR Res (2012)

Regulation of gene expression by peroxisome proliferator-activated receptors. The nuclear hormone receptor PPARα induces transcription through formation of a heterodimer with the retinoic X receptor and binding to peroxisome proliferator response elements (most are direct repeats with one intervening nucleotide) in the promoter of genes involved in fatty acid oxidation. PGC1α is an important PPARα coactivator in tissues that undergo extensive oxidative metabolism and induce mitochondrial expansion.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3369495&req=5

fig1: Regulation of gene expression by peroxisome proliferator-activated receptors. The nuclear hormone receptor PPARα induces transcription through formation of a heterodimer with the retinoic X receptor and binding to peroxisome proliferator response elements (most are direct repeats with one intervening nucleotide) in the promoter of genes involved in fatty acid oxidation. PGC1α is an important PPARα coactivator in tissues that undergo extensive oxidative metabolism and induce mitochondrial expansion.
Mentions: Peroxisome proliferator-activated receptor alpha (PPARα) is a member of the family of nuclear hormone receptors which function as ligand activated transcription factors, with a signature type II zinc finger DNA binding motif, to control the expression of specific genes involved in fatty acid utilization [19, 20] (Figure 1). Liver, muscle, kidney, and brown adipose tissue express high levels of PPARα [20, 21]. The endogenous ligands for PPARα activation include fatty acids and their metabolites [22]. PPARs control expression of genes by partnering with RXR and binding to peroxisome proliferator response elements (PPREs) in the promoter of target genes, ultimately resulting in the stimulation of FA oxidation. In mice, receptor agonists cause proliferation of peroxisomes which serve to oxidize long chain fatty acids and detoxify xenobiotic compounds [23]. PPARα is an activator of genes involved in β-oxidation including carnitine palmitoyl transferase 1 (CPT1α) and acyl-CoA oxidase (ACOX). In the liver, fatty acid oxidation is primarily regulated by the level of CPT1 [24]. CPT1α expression is controlled by a complex of transcription factors including PPARγ-coactivator 1 α (PGC1α) and PPARα [24]. CPT1 is found on the outer surface of the mitochondria and transports fatty acids into the mitochondria by the formation of an acyl-carnitine molecule. Upon entry into the inner side of the mitochondrial membrane, CPT2 removes the carnitine, reforming acyl-CoA [24].

Bottom Line: Studies in a multitude of models including cell culture, animal and clinical studies demonstrate that citrus-derived flavonoids have therapeutic potential to attenuate dyslipidemia, correct hyperinsulinemia and hyperglycemia, and reduce atherosclerosis.Emerging evidence suggests the metabolic regulators, PPARα and PGC1α, are targets of the citrus flavonoids, and their activation may be at least partially responsible for mediating their metabolic effects.Molecular studies will add significantly to the concept of these flavonoids as viable and promising therapeutic agents to treat the dysregulation of lipid homeostasis, metabolic disease, and its cardiovascular complications.

View Article: PubMed Central - PubMed

Affiliation: Vascular Biology Group, Robarts Research Institute, 100 Perth Drive, London, ON, Canada N6A 5K8.

ABSTRACT
Studies in a multitude of models including cell culture, animal and clinical studies demonstrate that citrus-derived flavonoids have therapeutic potential to attenuate dyslipidemia, correct hyperinsulinemia and hyperglycemia, and reduce atherosclerosis. Emerging evidence suggests the metabolic regulators, PPARα and PGC1α, are targets of the citrus flavonoids, and their activation may be at least partially responsible for mediating their metabolic effects. Molecular studies will add significantly to the concept of these flavonoids as viable and promising therapeutic agents to treat the dysregulation of lipid homeostasis, metabolic disease, and its cardiovascular complications.

No MeSH data available.


Related in: MedlinePlus