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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

Potential mechanisms for the reduction in risk factors for atherosclerosis by flavonoids. Both in vitro and in vivo data suggest that citrus flavonoids decrease macrophage uptake of oxidized LDL and macrophage CE accumulation and improve dyslipidemia. While the complete mechanisms have not been fully defined, the nuclear hormone receptors PPARα and PGC1α represent important molecular targets. The improvement in dyslipidemia can be linked to decreased VLDL secretion as hepatic lipid availability for storage or VLDL secretion is decreased as a consequence of PPAR-stimulated fatty acid oxidation. The oxidation of fatty acids by liver prevents ectopic lipid accumulation and improves both insulin sensitivity and glucose tolerance. Arrows indicate change in response to flavonoid treatment.
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Related In: Results  -  Collection


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fig2: Potential mechanisms for the reduction in risk factors for atherosclerosis by flavonoids. Both in vitro and in vivo data suggest that citrus flavonoids decrease macrophage uptake of oxidized LDL and macrophage CE accumulation and improve dyslipidemia. While the complete mechanisms have not been fully defined, the nuclear hormone receptors PPARα and PGC1α represent important molecular targets. The improvement in dyslipidemia can be linked to decreased VLDL secretion as hepatic lipid availability for storage or VLDL secretion is decreased as a consequence of PPAR-stimulated fatty acid oxidation. The oxidation of fatty acids by liver prevents ectopic lipid accumulation and improves both insulin sensitivity and glucose tolerance. Arrows indicate change in response to flavonoid treatment.

Mentions: Interestingly, in western diet-fed Ldlr−/− mice, naringenin did not stimulate fatty acid oxidation in muscle nor were any changes observed in the expression of genes linked to fatty acid oxidation, such as Cpt1β, Ucp1, and Ucp3 [45]. Instead, naringenin inhibited SREBP1c-mediated de novo lipogenesis and promoted glucose uptake. These results suggest that naringenin does not act directly on muscle. Reduced muscle lipid accumulation and improved glucose utilization in this model is consequent to attenuated de novo lipogenesis and decreased uptake of lipoprotein-derived lipid, the latter a consequence of decreased VLDL secretion. By increasing hepatic FA oxidation, naringenin permits glucose to be utilized by peripheral tissues, including muscle, resulting in the prevention of both lipid accumulation and insulin resistance (Figure 2). The protective effect of naringenin in preventing the metabolic disturbances associated with high-fat feeding was also observed in wild-type C57BL/6J mice. In this model, naringenin significantly reduced plasma and hepatic lipids, normalized glucose tolerance and insulin sensitivity and prevented obesity when compared to western-fed mice, although the time course for the preventative effect was significantly longer than that required for Ldlr−/− mice [45].


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)

Potential mechanisms for the reduction in risk factors for atherosclerosis by flavonoids. Both in vitro and in vivo data suggest that citrus flavonoids decrease macrophage uptake of oxidized LDL and macrophage CE accumulation and improve dyslipidemia. While the complete mechanisms have not been fully defined, the nuclear hormone receptors PPARα and PGC1α represent important molecular targets. The improvement in dyslipidemia can be linked to decreased VLDL secretion as hepatic lipid availability for storage or VLDL secretion is decreased as a consequence of PPAR-stimulated fatty acid oxidation. The oxidation of fatty acids by liver prevents ectopic lipid accumulation and improves both insulin sensitivity and glucose tolerance. Arrows indicate change in response to flavonoid treatment.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig2: Potential mechanisms for the reduction in risk factors for atherosclerosis by flavonoids. Both in vitro and in vivo data suggest that citrus flavonoids decrease macrophage uptake of oxidized LDL and macrophage CE accumulation and improve dyslipidemia. While the complete mechanisms have not been fully defined, the nuclear hormone receptors PPARα and PGC1α represent important molecular targets. The improvement in dyslipidemia can be linked to decreased VLDL secretion as hepatic lipid availability for storage or VLDL secretion is decreased as a consequence of PPAR-stimulated fatty acid oxidation. The oxidation of fatty acids by liver prevents ectopic lipid accumulation and improves both insulin sensitivity and glucose tolerance. Arrows indicate change in response to flavonoid treatment.
Mentions: Interestingly, in western diet-fed Ldlr−/− mice, naringenin did not stimulate fatty acid oxidation in muscle nor were any changes observed in the expression of genes linked to fatty acid oxidation, such as Cpt1β, Ucp1, and Ucp3 [45]. Instead, naringenin inhibited SREBP1c-mediated de novo lipogenesis and promoted glucose uptake. These results suggest that naringenin does not act directly on muscle. Reduced muscle lipid accumulation and improved glucose utilization in this model is consequent to attenuated de novo lipogenesis and decreased uptake of lipoprotein-derived lipid, the latter a consequence of decreased VLDL secretion. By increasing hepatic FA oxidation, naringenin permits glucose to be utilized by peripheral tissues, including muscle, resulting in the prevention of both lipid accumulation and insulin resistance (Figure 2). The protective effect of naringenin in preventing the metabolic disturbances associated with high-fat feeding was also observed in wild-type C57BL/6J mice. In this model, naringenin significantly reduced plasma and hepatic lipids, normalized glucose tolerance and insulin sensitivity and prevented obesity when compared to western-fed mice, although the time course for the preventative effect was significantly longer than that required for Ldlr−/− mice [45].

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