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Protopanaxatriol, a novel PPARγ antagonist from Panax ginseng, alleviates steatosis in mice.

Zhang Y, Yu L, Cai W, Fan S, Feng L, Ji G, Huang C - Sci Rep (2014)

Bottom Line: Obesity is prevalent worldwide, and is highly associated with metabolic disorders, such as insulin resistance, hyperlipidemia and steatosis.TR-FRET assay revealed that PPT was specifically bound to PPARγ LBD, which was further confirmed by the molecular docking study.Our findings shed new light on the mechanism of ginseng in the treatment of metabolic syndrome.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China.

ABSTRACT
Obesity is prevalent worldwide, and is highly associated with metabolic disorders, such as insulin resistance, hyperlipidemia and steatosis. Ginseng has been used as food and traditional herbal medicine for the treatment of various metabolic diseases. However, the molecular mechanisms how ginseng and its components participate in the regulation of lipogenesis are still largely unclear. Here, we identified that protopanaxatriol (PPT), a major ginseng constituent, inhibited rosiglitazone-supported adipocyte differentiation of 3T3-L1 cells by repressing the expression of lipogenesis-related gene expression. In high-fat diet-induced obesity (DIO) mice, PPT reduced body weight and serum lipid levels, improved insulin resistance, as well as morphology and lipid accumulation, particular macrovesicular steatosis, in the livers. These effects were confirmed with genetically obese ob/ob mice. A reporter gene assay showed that PPT specifically inhibited the transactivity of PPARγ, but not PPAR α, β/δ and LXR α, β. TR-FRET assay revealed that PPT was specifically bound to PPARγ LBD, which was further confirmed by the molecular docking study. Our data demonstrate that PPT is a novel PPARγ antagonist. The inhibition of PPARγ activity could be a promising therapy for obesity and steatosis. Our findings shed new light on the mechanism of ginseng in the treatment of metabolic syndrome.

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PPT is a natural antagonist of PPARγ.(a)-(c). PPT specially inhibits the transcription activity of PPARγ (a), but not PPARα (b) and PPARβ (c) PPT 10, PPT 25, PPT 50: 10, 25 and 50 μM PPT. The concentration of Rosiglitazone, WY14643 and GW0742 is 10 μM. (d) Binding of PPT on PPARγ-LBD in competition with rosiglitazone in a competitive TR-FRET assay. (e) The structure of the complex of the PPARγ LBD and PPT by molecular docking. (f) The 2D- interaction map of the complex of the PPARγ LBD and PPT. Data are presented as means ± SEM (n = 3). *P<0.05, **P<0.01vs. agonist group.
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f6: PPT is a natural antagonist of PPARγ.(a)-(c). PPT specially inhibits the transcription activity of PPARγ (a), but not PPARα (b) and PPARβ (c) PPT 10, PPT 25, PPT 50: 10, 25 and 50 μM PPT. The concentration of Rosiglitazone, WY14643 and GW0742 is 10 μM. (d) Binding of PPT on PPARγ-LBD in competition with rosiglitazone in a competitive TR-FRET assay. (e) The structure of the complex of the PPARγ LBD and PPT by molecular docking. (f) The 2D- interaction map of the complex of the PPARγ LBD and PPT. Data are presented as means ± SEM (n = 3). *P<0.05, **P<0.01vs. agonist group.

Mentions: Based on the inhibition of adipocyte differentiation, and the modulation of the expression of PPARγ and its downstream genes, we postulated that PPT might target PPARγ directly. To test this hypothesis, HEK293T cells were co-transfected with GAL4-PPARγ ligand-binding domain (LBD) fusion plasmid and a plasmid of the UAS reporter. Rosiglitazone could activate PPARγ transactivity, which was significantly inhibited by PPT (Fig. 6a). In contrast, PPT did not show an inhibitory effect on other nuclear receptors involved in metabolic disorders, such as PPARα and β/σ (Fig. 6b and 6c), LXRα and β (data not shown).


Protopanaxatriol, a novel PPARγ antagonist from Panax ginseng, alleviates steatosis in mice.

Zhang Y, Yu L, Cai W, Fan S, Feng L, Ji G, Huang C - Sci Rep (2014)

PPT is a natural antagonist of PPARγ.(a)-(c). PPT specially inhibits the transcription activity of PPARγ (a), but not PPARα (b) and PPARβ (c) PPT 10, PPT 25, PPT 50: 10, 25 and 50 μM PPT. The concentration of Rosiglitazone, WY14643 and GW0742 is 10 μM. (d) Binding of PPT on PPARγ-LBD in competition with rosiglitazone in a competitive TR-FRET assay. (e) The structure of the complex of the PPARγ LBD and PPT by molecular docking. (f) The 2D- interaction map of the complex of the PPARγ LBD and PPT. Data are presented as means ± SEM (n = 3). *P<0.05, **P<0.01vs. agonist group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4260220&req=5

f6: PPT is a natural antagonist of PPARγ.(a)-(c). PPT specially inhibits the transcription activity of PPARγ (a), but not PPARα (b) and PPARβ (c) PPT 10, PPT 25, PPT 50: 10, 25 and 50 μM PPT. The concentration of Rosiglitazone, WY14643 and GW0742 is 10 μM. (d) Binding of PPT on PPARγ-LBD in competition with rosiglitazone in a competitive TR-FRET assay. (e) The structure of the complex of the PPARγ LBD and PPT by molecular docking. (f) The 2D- interaction map of the complex of the PPARγ LBD and PPT. Data are presented as means ± SEM (n = 3). *P<0.05, **P<0.01vs. agonist group.
Mentions: Based on the inhibition of adipocyte differentiation, and the modulation of the expression of PPARγ and its downstream genes, we postulated that PPT might target PPARγ directly. To test this hypothesis, HEK293T cells were co-transfected with GAL4-PPARγ ligand-binding domain (LBD) fusion plasmid and a plasmid of the UAS reporter. Rosiglitazone could activate PPARγ transactivity, which was significantly inhibited by PPT (Fig. 6a). In contrast, PPT did not show an inhibitory effect on other nuclear receptors involved in metabolic disorders, such as PPARα and β/σ (Fig. 6b and 6c), LXRα and β (data not shown).

Bottom Line: Obesity is prevalent worldwide, and is highly associated with metabolic disorders, such as insulin resistance, hyperlipidemia and steatosis.TR-FRET assay revealed that PPT was specifically bound to PPARγ LBD, which was further confirmed by the molecular docking study.Our findings shed new light on the mechanism of ginseng in the treatment of metabolic syndrome.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China.

ABSTRACT
Obesity is prevalent worldwide, and is highly associated with metabolic disorders, such as insulin resistance, hyperlipidemia and steatosis. Ginseng has been used as food and traditional herbal medicine for the treatment of various metabolic diseases. However, the molecular mechanisms how ginseng and its components participate in the regulation of lipogenesis are still largely unclear. Here, we identified that protopanaxatriol (PPT), a major ginseng constituent, inhibited rosiglitazone-supported adipocyte differentiation of 3T3-L1 cells by repressing the expression of lipogenesis-related gene expression. In high-fat diet-induced obesity (DIO) mice, PPT reduced body weight and serum lipid levels, improved insulin resistance, as well as morphology and lipid accumulation, particular macrovesicular steatosis, in the livers. These effects were confirmed with genetically obese ob/ob mice. A reporter gene assay showed that PPT specifically inhibited the transactivity of PPARγ, but not PPAR α, β/δ and LXR α, β. TR-FRET assay revealed that PPT was specifically bound to PPARγ LBD, which was further confirmed by the molecular docking study. Our data demonstrate that PPT is a novel PPARγ antagonist. The inhibition of PPARγ activity could be a promising therapy for obesity and steatosis. Our findings shed new light on the mechanism of ginseng in the treatment of metabolic syndrome.

Show MeSH
Related in: MedlinePlus