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Molecules
2021 Aug 23;2616:. doi: 10.3390/molecules26165094.
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Acanthaster planci Inhibits PCSK9 and Lowers Cholesterol Levels in Rats.
Kamaruddin NN
,
Hajri NA
,
Andriani Y
,
Abdul Manan AF
,
Tengku Muhammad TS
,
Mohamad H
.
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Atherosclerosis is the main cause of cardiovascular diseases which in turn, lead to the highest number of mortalities globally. This pathophysiological condition is developed due to a constant elevated level of plasma cholesterols. Statin is currently the widely used treatment in reducing the level of cholesterols, however, it may cause adverse side effects. Therefore, there is an urgent need to search for new alternative treatment. PCSK9 is an enzyme responsible in directing LDL-receptor (LDL-R)/LDL-cholesterols (LDL-C) complex to lysosomal degradation, preventing the receptor from recycling back to the surface of liver cells. Therefore, PCSK9 offers a potential target to search for small molecule inhibitors which inhibit the function of this enzyme. In this study, a marine invertebrate Acanthaster planci, was used to investigate its potential in inhibiting PCSK9 and lowering the levels of cholesterols. Cytotoxicity activity of A. planci on human liver HepG2 cells was carried out using the MTS assay. It was found that methanolic extract and fractions did not exhibit cytotoxicity effect on HepG2 cell line with IC50 values of more than 30 µg/mL. A compound deoxythymidine also did not exert any cytotoxicity activity with IC50 value of more than 4 µg/mL. Transient transfection and luciferase assay were conducted to determine the effects of A. planci on the transcriptional activity of PCSK9 promoter. Methanolic extract and Fraction 2 (EF2) produced the lowest reduction in PCSK9 promoter activity to 70 and 20% of control at 12.5 and 6.25 μg/mL, respectively. In addition, deoxythymidine also decreased PCSK9 promoter activity to the lowest level of 60% control at 3.13 μM. An in vivo study using Sprague Dawley rats demonstrated that 50 and 100 mg/kg of A. planci methanolic extract reduced the total cholesterols and LDL-C levels to almost similar levels of untreated controls. The level of serum glutamate oxalate transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) showed that the administration of the extract did not produce any toxicity effect and cause any damage to rat liver. The results strongly indicate that A. planci produced a significant inhibitory activity on PCSK9 gene expression in HepG2 cells which may be responsible for inducing the uptake of cholesterols by liver, thus, reducing the circulating levels of total cholesterols and LDL-C. Interestingly, A. planci also did show any adverse hepato-cytotoxicity and toxic effects on liver. Thus, this study strongly suggests that A. planci has a vast potential to be further developed as a new class of therapeutic agent in lowering the blood cholesterols and reducing the progression of atherosclerosis.
Figure 1. Percentage of cell growth of HepG2 cell line after the treatment of A. planci methanolic extract for 72 h. The cells were treated at various concentrations of the extract from 6.25 to 200 µg/mL. The value in the untreated control was assigned as 100% and the values in the treated samples were relative to the untreated control value. Data presented as mean ± standard deviation (SD) with n = 6. * denotes significantly different as compared to DMSO-treated cells (negative control) at p < 0.05. DMSO was used as the carrier to dissolve and dilute the extract.
Figure 2. Percentage of cell growth of HepG2 after the treatment with A. planci fractions at five different concentrations from 3.13 to 50 µg/mL for 72 h. The percentage of cell growth was compared to the negative control of 1% (v/v) of DMSO which was used as the carrier. Data obtained presented as mean ± SD with n = 6. EF represents the fraction number. * denotes significantly different as compared to DMSO-treated cells (negative control) at p < 0.05. DMSO was used as the carrier to dissolve and dilute the extract.
Figure 3. Luciferase activity of HepG2 cells transfected with PCSK9 promoter-reporter construct after 24 h treatment with A. planci methanolic extract. The cells were treated at various concentrations from 3.13 to 50 µg/mL. Data presented as mean ± SD with n = 6. The value at each point represents the fold change of normalised PCSK9 promoter activity relative to the untreated control which was assigned as 100%. * denotes significantly different as compared to DMSO-treated cells (negative control) at p < 0.05. DMSO was used as the carrier to dissolve and dilute the extract.
Figure 4. Luciferase activity of HepG2 cells transfected with PCSK9 promoter-reporter construct after 24 h treatment with A. planci fractions. The treatments were at five different concentrations from 3.13 to 50 µg/mL. Data presented as mean ± SD with n = 6. The value at each point represents the fold change of normalised PCSK9 promoter activity relative to the untreated control which is assigned as 100%. * denotes significantly different as compared to DMSO-treated cells (negative control) at p < 0.05. DMSO was used as the carrier to dissolve and dilute the extract.
Figure 5. Percentage of cell growth of HepG2 cells after the treatment with deoxythymidine for 72 h (A). Luciferase activity of HepG2 transfected with PCSK9 promoter-reporter construct after 24 h treatment with deoxythymidine (B). The cells were treated at various concentrations from 3.13 to 50 µM. Data presented as mean ± SD with n = 6. The values were compared to the negative control. * denotes significantly different as compared to DMSO-treated cells (negative control) at p < 0.05. DMSO was used as the carrier to dissolve and dilute the extract.
Figure 6. The changes of total cholesterol levels in rats fed with normal diet throughout 42 days of the experimental period. (A) Fed with normal diet for 14 days, followed by high fat diet for another 14 days, followed by normal diet until Day 42 (B); fed with high fat diet for 14 days, followed by normal diet together with atorvastatin for another 14 days, followed by normal diet without atorvastatin until Day 42 (C); fed with high fat diet for 14 days, followed by normal diet together with 100 mg/kg of methanolic extract for another 14 days, followed by normal diet without the extract until Day 42 (D); and fed with high fat diet for 14 days, followed by normal diet together with 50 mg/kg of methanolic extract for another 14 days, followed by normal diet without the extract until Day 42 (E). * denotes significantly different as compared to untreated control rats at Day 0 (negative control) of the respective group at p < 0.05.
Figure 7. The changes of LDL-C (mg/dL) level in rats fed with normal diet throughout 42 days of the experimental period. (A) Fed with normal diet for 14 days, followed by high fat diet for another 14 days, followed by normal diet until Day 42 (B); fed with high fat diet for 14 days, followed by normal diet together with atorvastatin for another 14 days, followed by normal diet without atorvastatin until Day 42 (C); fed with high fat diet for 14 days, followed by normal diet together with 100 mg/kg of methanolic extract for another 14 days, followed by normal diet without the extract until Day 42 (D); and fed with high fat diet for 14 days, followed by normal diet together with 50 mg/kg of methanolic extract for another 14 days, followed by normal diet without the extract until Day 42 (E). * denotes significantly different as compared to untreated control rats at Day 0 (negative control) of the respective group at p < 0.05.
Figure 8. The changes of triglyceride (TG) levels in rats fed with normal diet throughout 42 days of the experimental period. (A) Fed with normal diet for 14 days, followed by high fat diet for another 14 days, followed by normal diet until Day 42 (B); fed with high fat diet for 14 days, followed by normal diet together with atorvastatin for another 14 days, followed by normal diet without atorvastatin until Day 42 (C); fed with high fat diet for 14 days, followed by normal diet together with 100 mg/kg of methanolic extract for another 14 days, followed by normal diet without the extract until Day 42 (D); and fed with high fat diet for 14 days, followed by normal diet together with 50 mg/kg of methanolic extract for another 14 days, followed by normal diet without the extract until Day 42 (E). * denotes significantly different as compared to untreated control rats at Day 0 (negative control) of the respective group at p < 0.05.
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