<i>Acanthaster planci</i> Inhibits PCSK9 and Lowers Cholesterol Levels in Rats
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...
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MDPI AG
2021-08-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/26/16/5094 |
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| author | Nurjannatul Naim Kamaruddin Nor Azwin Hajri Yosie Andriani Aina Farahiyah Abdul Manan Tengku Sifzizul Tengku Muhammad Habsah Mohamad |
| author_facet | Nurjannatul Naim Kamaruddin Nor Azwin Hajri Yosie Andriani Aina Farahiyah Abdul Manan Tengku Sifzizul Tengku Muhammad Habsah Mohamad |
| author_sort | Nurjannatul Naim Kamaruddin |
| collection | DOAJ |
| description | 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 <i>Acanthaster planci</i>, was used to investigate its potential in inhibiting PCSK9 and lowering the levels of cholesterols. Cytotoxicity activity of <i>A. planci</i> 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 IC<sub>50</sub> values of more than 30 µg/mL. A compound deoxythymidine also did not exert any cytotoxicity activity with IC<sub>50</sub> value of more than 4 µg/mL. Transient transfection and luciferase assay were conducted to determine the effects of <i>A. planci</i> 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 <i>A. planci</i> 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 <i>A. planci</i> 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 <i>A. planci</i> 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. |
| first_indexed | 2024-03-10T08:32:44Z |
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| id | doaj.art-f17c53646aa240498bf9d5ab8f387f52 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T08:32:44Z |
| publishDate | 2021-08-01 |
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| series | Molecules |
| spelling | doaj.art-f17c53646aa240498bf9d5ab8f387f522023-11-22T08:56:34ZengMDPI AGMolecules1420-30492021-08-012616509410.3390/molecules26165094<i>Acanthaster planci</i> Inhibits PCSK9 and Lowers Cholesterol Levels in RatsNurjannatul Naim Kamaruddin0Nor Azwin Hajri1Yosie Andriani2Aina Farahiyah Abdul Manan3Tengku Sifzizul Tengku Muhammad4Habsah Mohamad5Institute of Marine Biotechnology, Universiti Malaysia Terengganu, Kuala Nerus 21030, MalaysiaInstitute of Marine Biotechnology, Universiti Malaysia Terengganu, Kuala Nerus 21030, MalaysiaInstitute of Marine Biotechnology, Universiti Malaysia Terengganu, Kuala Nerus 21030, MalaysiaInstitute of Marine Biotechnology, Universiti Malaysia Terengganu, Kuala Nerus 21030, MalaysiaInstitute of Marine Biotechnology, Universiti Malaysia Terengganu, Kuala Nerus 21030, MalaysiaInstitute of Marine Biotechnology, Universiti Malaysia Terengganu, Kuala Nerus 21030, MalaysiaAtherosclerosis 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 <i>Acanthaster planci</i>, was used to investigate its potential in inhibiting PCSK9 and lowering the levels of cholesterols. Cytotoxicity activity of <i>A. planci</i> 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 IC<sub>50</sub> values of more than 30 µg/mL. A compound deoxythymidine also did not exert any cytotoxicity activity with IC<sub>50</sub> value of more than 4 µg/mL. Transient transfection and luciferase assay were conducted to determine the effects of <i>A. planci</i> 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 <i>A. planci</i> 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 <i>A. planci</i> 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 <i>A. planci</i> 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.https://www.mdpi.com/1420-3049/26/16/5094<i>Acanthaster planci</i>PCSK9atherosclerosisLDL-receptorLDL-cholesterol |
| spellingShingle | Nurjannatul Naim Kamaruddin Nor Azwin Hajri Yosie Andriani Aina Farahiyah Abdul Manan Tengku Sifzizul Tengku Muhammad Habsah Mohamad <i>Acanthaster planci</i> Inhibits PCSK9 and Lowers Cholesterol Levels in Rats Molecules <i>Acanthaster planci</i> PCSK9 atherosclerosis LDL-receptor LDL-cholesterol |
| title | <i>Acanthaster planci</i> Inhibits PCSK9 and Lowers Cholesterol Levels in Rats |
| title_full | <i>Acanthaster planci</i> Inhibits PCSK9 and Lowers Cholesterol Levels in Rats |
| title_fullStr | <i>Acanthaster planci</i> Inhibits PCSK9 and Lowers Cholesterol Levels in Rats |
| title_full_unstemmed | <i>Acanthaster planci</i> Inhibits PCSK9 and Lowers Cholesterol Levels in Rats |
| title_short | <i>Acanthaster planci</i> Inhibits PCSK9 and Lowers Cholesterol Levels in Rats |
| title_sort | i acanthaster planci i inhibits pcsk9 and lowers cholesterol levels in rats |
| topic | <i>Acanthaster planci</i> PCSK9 atherosclerosis LDL-receptor LDL-cholesterol |
| url | https://www.mdpi.com/1420-3049/26/16/5094 |
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