Li X et al. (2022), Sea Cucumber Saponins Derivatives Alleviate Hep...

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Mar Drugs 2022 Nov 10;2011:. doi: 10.3390/md20110703.

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Sea Cucumber Saponins Derivatives Alleviate Hepatic Lipid Accumulation Effectively in Fatty Acids-Induced HepG2 Cells and Orotic Acid-Induced Rats.

Li X , Zeng B , Wen L , Zhao Y , Li Z , Xue C , Zhang T , Wang Y .

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The sulfated echinoside A (EA) and holothurin A (HA) are two prominent saponins in sea cucumber with high hemolytic activity but also superior lipid-lowering activity. Deglycosylated derivatives EA2 and HA2 exhibit low hemolysis compared to EA and HA, but their efficacies on lipid metabolism regulation remains unknown. In this study, fatty acids-treated HepG2 cells and orotic acid-treated rats were used to investigate the lipid-lowering effects of sea cucumber saponin derivatives. Both the saponin and derivatives could effectively alleviate lipid accumulation in HepG2 model, especially EA and EA2. Moreover, though the lipid-lowering effect of EA2 was not equal with EA at the same dosage of 0.05% in diet, 0.15% dosage of EA2 significantly reduced hepatic steatosis rate, liver TC and TG contents by 76%, 41.5%, and 63.7%, respectively, compared to control and reversed liver histopathological features to normal degree according to H&E stained sections. Possible mechanisms mainly included enhancement of fatty acids β-oxidation and cholesterol catabolism through bile acids synthesis and excretion, suppression of lipogenesis and cholesterol uptake. It revealed that the efficacy of EA2 on lipid metabolism regulation was dose-dependent, and 0.15% dosage of EA2 possessed better efficacy with lower toxicity compared to 0.05% dosage of EA.

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	Figure 1. Chemical structure of sea cucumber saponins EA (A), HA (B), and their derivatives EA2 (C) and HA2 (D).
	Figure 2. Effects of sea cucumber saponins, derivatives and ginsenoside Rh2 on lipid accumulation in HepG2 cells. Cells were treated as follows, N: serum-free DMEM containing 10% BSA; Con: serum-free DMEM containing 10% BSA and 1 μM free fatty acids (FFA); HA, HA2, EA, EA2, RH2: serum-free DMEM containing 10% BSA, 1μM FFA, and 0.8 μM saponins. After the incubation for 24 h, lipid accumulation was assessed by oil red O staining (A–G) and intracellular TG contents normalized as the amount of cellular protein (mg/g protein) (H). A: normal; B: control; C: HA; D: HA2; E: EA; F: EA2; G: RH2. Data were presented as Mean ± SEM. ** p < 0.01 indicates significant differences between normal and control group. Different letters represented significant differences at p < 0.05 among control and treated groups.
	Figure 3. Effects of sea cucumber saponins, derivatives, and ginsenoside Rh2 on the protein expression levels of genes related to hepatic lipogenesis and fatty acid β-oxidation in HepG2 cells. Cells were treated as follows, Con: serum-free DMEM containing 10% BSA; M: serum-free DMEM containing 10% BSA and 1 μM FFA; HA, HA2, EA, EA2, RH2: serum-free DMEM containing 10% BSA, 1 μM FFA, and 0.8 μM saponins. (A) SCD-1, stearoyl-CoA desaturase 1; (B) SREBP-1, sterol regulatory element binding transcription factor 1; (C) FAS, fatty acid synthase; (D) ACC-1, acetyl-CoA carboxylase; (E) CPT-1A, carnitine palmitoyltransferase 1A; (F) ACOX-1, Acyl-CoA oxidase 1. Data were presented as Mean ± SEM. ** p < 0.01 indicates significant differences between normal and control group. Different letters represented significant differences at p < 0.05 among control and treated groups.
	Figure 4. Effects of EA (0.05%), EA2 (0.05%) and EA2 -H (0.15%) on liver histopathological features and lipids deposition. Rats were fed as follows, N: normal diet; Con: normal diet supplemented with 1% orotic acid; EA, EA2: normal diet supplemented with 1% orotic acid and 0.05% EA or EA2; EA2-H: normal diet supplemented with 1% orotic acid and 0.15% EA2. Detection of liver histological features by hematoxylin-eosin (HE) staining. (A) N, (B) control, (C) EA (0.05%), (D) EA2 (0.05%), (E) EA2-H (0.15%). (F) Hepatic steatosis rate was calculated according to white areas fraction with three different views for each rat in H&E staining slices by image j. Detection of hepatic lipids accumulation by oil red O staining. (G) N, (H) control, (I) EA (0.05%), (J) EA2 (0.05%), (K) EA2-H (0.15%). Data were presented as Mean ± SEM. ** p < 0.01 indicates significant differences between normal and control group. Different letters represented significant differences at p < 0.05 among control and treated groups.
	Figure 5. Effects of EA (0.05%), EA2 (0.05%) and EA2-H (0.15%) on hepatic lipids and liver injury. Rats were fed as follows, N: normal diet; Con: normal diet supplemented with 1% orotic acid; EA, EA2: normal diet supplemented with 1% orotic acid and 0.05% EA or EA2; EA2-H: normal diet supplemented with 1% orotic acid and 0.15%. (A) Hepatic index (mass ratio of liver to body); (B) Liver TC; (C) Liver TG. (D) Serum ALT; (E) Serum AST. Data were presented as Mean ± SEM. ** p < 0.01 indicates significant differences between normal and control group. Different letters represented significant differences at p < 0.05 among control and treated groups.
	Figure 6. Effects of EA (0.05%), EA2 (0.05%), and EA2-H (0.15%) on fecal lipids. Rats were fed as follows, N: normal diet; Con: normal diet supplemented with 1% orotic acid; EA, EA2: normal diet supplemented with 1% orotic acid and 0.05% EA or EA2; EA2-H: normal diet supplemented with 1% orotic acid and 0.15%. (A) Fecal total lipids; (B) fecal neutral sterols; (C) fecal total bile acids. Data were presented as Mean ± SEM. p < 0.01 indicates significant differences between normal and control group. Different letters represented significant differences at p < 0.05 among control and treated groups.
	Figure 7. Effects of EA and EA2-H on the expressions of genes related to fatty acids metabolism (A) and cholesterol metabolism (B) according to RNA-Seq results. The gene lists were obtained from KEGG and ordered randomly.
	Figure 8. Possible mechanisms of sea cucumber saponins and their derivatives on alleviating hepatic lipid accumulation in fatty acids-treated HepG2 cells and orotic acid-treated rats.

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