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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 ameliorates hepatic steatosis in high-fat diet–induced obesity C57BL/6 mice.(a) H&E and Oil red O staining of liver sections (×200). (b) Liver TG level. (c) Liver TC level. (d) Serum AST level. (e) Serum ALT level. (f) Liver LPO (lipid peroxide) content. (g) Liver glutathione content. (h) Mitochondrial respiratory chain level. (i) Serum IL-1β content. (j) Serum IL-6 content. Data are presented as means ± SEM (n = 8). *P<0.05, **P<0.01vs. HF group.
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f3: PPT ameliorates hepatic steatosis in high-fat diet–induced obesity C57BL/6 mice.(a) H&E and Oil red O staining of liver sections (×200). (b) Liver TG level. (c) Liver TC level. (d) Serum AST level. (e) Serum ALT level. (f) Liver LPO (lipid peroxide) content. (g) Liver glutathione content. (h) Mitochondrial respiratory chain level. (i) Serum IL-1β content. (j) Serum IL-6 content. Data are presented as means ± SEM (n = 8). *P<0.05, **P<0.01vs. HF group.

Mentions: Since a high-fat diet induces fatty liver in mice, we further assessed whether PPT could ameliorate the hepatic steatosis by examining the morphology and lipid accumulation in the liver sections. Compared to that of chow diet-fed mice, more fat droplets, microvesicular and macrovesicular were observed in most hepatocytes of the DIO mice (Fig. 3a). In addition, seven of DIO mice displayed grade 3 (>66%) steatosis, and one mouse had grade 2 (33%–66%) steatosis. In 50% to 70% of hepatocytes, fat was seen mostly as macrovesicular droplets, and 30%–50% of the hepatocytes remained microvesicular steatosis. Biochemistry analysis of hepatic TG content revealed that the amount of TG was significantly increased in DIO mice (Fig. 3b). PPT treatment decreased steatosis by reducing macrovacuolar droplets in liver section. Among PPT-treated mice, seven mice displayed grade 1 (5%–33%) steatosis, and one mouse had grade 2 (33%–66%) steatosis, indicating PPT treatment may prevent or reverse the lipid accumulation in the DIO mice. Also, liver TG concentration was decreased in PPT-treated animals (P <0.05 vs. DIO mice) (Fig. 3b). However, PPT treatment did not reduce the TC content in the liver of DIO mice (Fig. 3c). Furthermore, PPT lowered the serum AST and ALT levels in DIO mice (Fig. 3d and 3e), indicating that PPT has the capacity to improve liver damage. These results suggest that PPT may prevent lipid accumulation and block the development of hepatic steatosis induced by a high-fat diet in mice.


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 ameliorates hepatic steatosis in high-fat diet–induced obesity C57BL/6 mice.(a) H&E and Oil red O staining of liver sections (×200). (b) Liver TG level. (c) Liver TC level. (d) Serum AST level. (e) Serum ALT level. (f) Liver LPO (lipid peroxide) content. (g) Liver glutathione content. (h) Mitochondrial respiratory chain level. (i) Serum IL-1β content. (j) Serum IL-6 content. Data are presented as means ± SEM (n = 8). *P<0.05, **P<0.01vs. HF group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: PPT ameliorates hepatic steatosis in high-fat diet–induced obesity C57BL/6 mice.(a) H&E and Oil red O staining of liver sections (×200). (b) Liver TG level. (c) Liver TC level. (d) Serum AST level. (e) Serum ALT level. (f) Liver LPO (lipid peroxide) content. (g) Liver glutathione content. (h) Mitochondrial respiratory chain level. (i) Serum IL-1β content. (j) Serum IL-6 content. Data are presented as means ± SEM (n = 8). *P<0.05, **P<0.01vs. HF group.
Mentions: Since a high-fat diet induces fatty liver in mice, we further assessed whether PPT could ameliorate the hepatic steatosis by examining the morphology and lipid accumulation in the liver sections. Compared to that of chow diet-fed mice, more fat droplets, microvesicular and macrovesicular were observed in most hepatocytes of the DIO mice (Fig. 3a). In addition, seven of DIO mice displayed grade 3 (>66%) steatosis, and one mouse had grade 2 (33%–66%) steatosis. In 50% to 70% of hepatocytes, fat was seen mostly as macrovesicular droplets, and 30%–50% of the hepatocytes remained microvesicular steatosis. Biochemistry analysis of hepatic TG content revealed that the amount of TG was significantly increased in DIO mice (Fig. 3b). PPT treatment decreased steatosis by reducing macrovacuolar droplets in liver section. Among PPT-treated mice, seven mice displayed grade 1 (5%–33%) steatosis, and one mouse had grade 2 (33%–66%) steatosis, indicating PPT treatment may prevent or reverse the lipid accumulation in the DIO mice. Also, liver TG concentration was decreased in PPT-treated animals (P <0.05 vs. DIO mice) (Fig. 3b). However, PPT treatment did not reduce the TC content in the liver of DIO mice (Fig. 3c). Furthermore, PPT lowered the serum AST and ALT levels in DIO mice (Fig. 3d and 3e), indicating that PPT has the capacity to improve liver damage. These results suggest that PPT may prevent lipid accumulation and block the development of hepatic steatosis induced by a high-fat diet in mice.

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