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. 2024 Aug 28;29(17):4080.
doi: 10.3390/molecules29174080.

Gypensapogenin A-Liposomes Efficiently Ameliorates Hepatocellular Lipid Accumulation via Activation of FXR Receptor

Yidan Deng  1 , Jianmei Wang  1 , Di Wu  1   2 , Lin Qin  1   2 , Yuqi He  1   2 , Daopeng Tan  1   2
Affiliations

Gypensapogenin A-Liposomes Efficiently Ameliorates Hepatocellular Lipid Accumulation via Activation of FXR Receptor

Yidan Deng et al. Molecules. .

Abstract

Non-alcoholic fatty liver disease (NAFLD) is one of the most common metabolic diseases encountered in clinical practice, which is characterized by the excessive accumulation of triglycerides (steatosis), and a variety of metabolic abnormalities including lipid metabolism and bile acid metabolism are closely related to NAFLD. In China, Gynostemma pentaphyllum is used as functional food and Chinese medicine to treat various diseases, especially NAFLD, for a long time. However, the active components that exert the main therapeutic effects and their mechanisms remain unclear. In this study, Gypensapogenin A was isolated from the total saponins of G. pentaphyllum and prepared as a liposomal delivery system. Gypensapogenin A liposomes could activate FXR, inhibit the expression of CYP7A1 and CYP8B1, increase the expression of CYP27A1, modulate the ratio of CA and CDCA, decrease the content of CA, and increase the content of CDCA, thus forming a virtuous cycle of activating FXR to play a role in lowering blood lipid levels.

Keywords: FXR; Gynostemma pentaphyllum; Gypensapogenin A; bile acids; hyperlipidemia.

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Conflict of interest statement

The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Characterization and druglikeness of GpA. (A) Chromatographic characterization of Gp A; (B) the molecular docking of GypA with FXR; Golden of Figure 1B represents the structure of GpA; Blue of Figure 1B represents the amino acids of FXR protein. Black dotted lines represent hydrogen bonds; (C) prediction of druglikeness properties of GypA by SwissADME. The pink area of Figure 1C represents the optimal range for each property (lipophilicity: XLOGP3 between −0.7 and +5.0, size: MW between 150 and 500 g/mol, polarity: TPSA between 20 and 130 Å2, insolubility: logS not higher than 6, insaturation: fraction of carbons in the sp3 hybridization not less than 0.25, and flexibility: no more than 9 rotatable bonds).
Figure 2
Figure 2
Characterization of GpA-Lip. (A) The samples of GpA-Lip and Blank-Lip; (B) particle sizes distribution of GpA-Lip; (C) the TEM images of GpA-Lip (scale bars = 2000 nm or 600 nm); (D) Cell uptake images of Coumarin-6 liposome (scale bars = 25 μm).
Figure 3
Figure 3
Effect of Gyp A-Lip on the amelioration of hepatocellular lipid accumulation. (A) Oil red O staining of the cells; (B) effect of GpA-Lip on biochemical indices of high-fat model cells. vs. Model (* p < 0.05, ** p < 0.01); vs. Control (## p < 0.01).
Figure 4
Figure 4
Effect of GpA-Lip on bile acids in high-fat model cells. vs. Model (* p < 0.05); vs. Control (# p < 0.05, ## p < 0.01).
Figure 5
Figure 5
Effect of GpA-Lip on bile acid metabolizing enzymes. (A) Effect of GpA-Lip on the mRNA of bile acid metabolizing enzymes; (B) the expression of FXR, SHP and CYP7A1 proteins measured by western blotting; (C) effect of GpA-Lip on protein expression of FXR and CYP7A1. vs. Model (** p < 0.01); vs. Control (# p < 0.05, ## p < 0.01).
Figure 6
Figure 6
Effect of GpA-Lip on FXR knockdown cells. (A) FXR knockdown cell model construction; (B) changes in mRNA expression of key enzymes of the bile acid pathway in FXR knockdown cells; (C) FXR protein expression in different cells measured by western blotting; (D) effect of GpA-Lip on lipid accumulation in FXR knockdown cells; (E) effect of GpA-Lip on biochemical parameters in FXR knockdown cells; (F) effect of GpA-Lip on mRNA of key enzymes of the bile acid pathway in FXR knockdown cells; (G) the expression of FXR, SHP and CYP7A1 proteins in FXR knockdown cells measured by western blotting; (H) effect of GpA-Lip on protein expression of FXR and CYP7A1 in FXR knockdown cells. vs. sh FXR (* p < 0.05, ** p < 0.01); vs. Control (# p < 0.05, ## p < 0.01).
Figure 6
Figure 6
Effect of GpA-Lip on FXR knockdown cells. (A) FXR knockdown cell model construction; (B) changes in mRNA expression of key enzymes of the bile acid pathway in FXR knockdown cells; (C) FXR protein expression in different cells measured by western blotting; (D) effect of GpA-Lip on lipid accumulation in FXR knockdown cells; (E) effect of GpA-Lip on biochemical parameters in FXR knockdown cells; (F) effect of GpA-Lip on mRNA of key enzymes of the bile acid pathway in FXR knockdown cells; (G) the expression of FXR, SHP and CYP7A1 proteins in FXR knockdown cells measured by western blotting; (H) effect of GpA-Lip on protein expression of FXR and CYP7A1 in FXR knockdown cells. vs. sh FXR (* p < 0.05, ** p < 0.01); vs. Control (# p < 0.05, ## p < 0.01).
Figure 7
Figure 7
The potential mechanisms of GpA-Lip ameliorated hepatocellular lipid accumulation.
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