Click
here to close Hello! We notice that
you are using Internet Explorer, which is not supported by Echinobase
and may cause the site to display incorrectly. We suggest using a
current version of Chrome,
FireFox,
or Safari.
Molecules
2021 Aug 23;2616:. doi: 10.3390/molecules26165094.
Show Gene links
Show Anatomy links
Acanthaster planci Inhibits PCSK9 and Lowers Cholesterol Levels in Rats.
Kamaruddin NN
,
Hajri NA
,
Andriani Y
,
Abdul Manan AF
,
Tengku Muhammad TS
,
Mohamad H
.
???displayArticle.abstract???
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.
Akpanabiatu,
Rat serum electrolytes, lipid profile and cardiovascular activity onNauclea latifolia leaf extract administration.
2005, Pubmed
Akpanabiatu,
Rat serum electrolytes, lipid profile and cardiovascular activity onNauclea latifolia leaf extract administration.
2005,
Pubmed
Akyea,
Sub-optimal cholesterol response to initiation of statins and future risk of cardiovascular disease.
2019,
Pubmed
Al-Najjar,
Discovery of new nanomolar peroxisome proliferator-activated receptor γ activators via elaborate ligand-based modeling.
2011,
Pubmed
AlSharari,
Rutin Attenuates Hepatotoxicity in High-Cholesterol-Diet-Fed Rats.
2016,
Pubmed
Andersson,
Biological activity of saponins and saponin-like compounds from starfish and brittle-stars.
1989,
Pubmed
,
Echinobase
Andriani,
Antihypercholesterolemic and antiatherosclerotic potencies of Pandanus tectorius fruits via increasing scavenger receptor-B1 genes expression and inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity.
2020,
Pubmed
Barquera,
Global Overview of the Epidemiology of Atherosclerotic Cardiovascular Disease.
2015,
Pubmed
Baum,
PCSK9 inhibitor valuation: A science-based review of the two recent models.
2018,
Pubmed
Bordbar,
High-value components and bioactives from sea cucumbers for functional foods--a review.
2011,
Pubmed
,
Echinobase
Cameron,
Berberine decreases PCSK9 expression in HepG2 cells.
2008,
Pubmed
Catapano,
The safety of therapeutic monoclonal antibodies: implications for cardiovascular disease and targeting the PCSK9 pathway.
2013,
Pubmed
Chang,
The Cholesterol-Modulating Effect of Methanol Extract of Pigeon Pea (Cajanus cajan (L.) Millsp.) Leaves on Regulating LDLR and PCSK9 Expression in HepG2 Cells.
2019,
Pubmed
Chaudhary,
PCSK9 inhibitors: A new era of lipid lowering therapy.
2017,
Pubmed
Choi,
Welsh onion extract inhibits PCSK9 expression contributing to the maintenance of the LDLR level under lipid depletion conditions of HepG2 cells.
2017,
Pubmed
Cui,
Antiproliferative Activity, Proapoptotic Effect, and Cell Cycle Arrest in Human Cancer Cells of Some Marine Natural Product Extract.
2020,
Pubmed
,
Echinobase
Cui,
Beneficial impact of epigallocatechingallate on LDL-C through PCSK9/LDLR pathway by blocking HNF1α and activating FoxO3a.
2020,
Pubmed
Davis,
Acid-dependent ligand dissociation and recycling of LDL receptor mediated by growth factor homology region.
NULL,
Pubmed
Deepa,
Atheroprotective effect of exogenous heparin-derivative treatment on the aortic disturbances and lipoprotein oxidation in hypercholesterolemic diet fed rats.
2005,
Pubmed
Dong,
Chemical constituents and bioactivities of starfish.
2011,
Pubmed
,
Echinobase
Dressel,
Cost effectiveness of lifelong therapy with PCSK9 inhibitors for lowering cardiovascular events in patients with stable coronary artery disease: Insights from the Ludwigshafen Risk and Cardiovascular Health cohort.
2019,
Pubmed
Duan,
Peroxisome Proliferator-activated receptor γ activation by ligands and dephosphorylation induces proprotein convertase subtilisin kexin type 9 and low density lipoprotein receptor expression.
2012,
Pubmed
Eguchi,
Manzamine A, a marine-derived alkaloid, inhibits accumulation of cholesterol ester in macrophages and suppresses hyperlipidemia and atherosclerosis in vivo.
2013,
Pubmed
Ference,
Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel.
2017,
Pubmed
Furman,
Phosphorylation of 3'-azido-3'-deoxythymidine and selective interaction of the 5'-triphosphate with human immunodeficiency virus reverse transcriptase.
1986,
Pubmed
Gerwick,
Lessons from the past and charting the future of marine natural products drug discovery and chemical biology.
2012,
Pubmed
Gilat,
Prevention of diet-induced fatty liver in experimental animals by the oral administration of a fatty acid bile acid conjugate (FABAC).
2003,
Pubmed
Glerup,
Physiological and therapeutic regulation of PCSK9 activity in cardiovascular disease.
2017,
Pubmed
Hwang,
The Cholesterol-Lowering Effect of Capsella Bursa-Pastoris Is Mediated via SREBP2 and HNF-1α-Regulated PCSK9 Inhibition in Obese Mice and HepG2 Cells.
2021,
Pubmed
Jeong,
Mild hepatic fibrosis in cholesterol and sodium cholate diet-fed rats.
2005,
Pubmed
Jeong,
Sterol-dependent regulation of proprotein convertase subtilisin/kexin type 9 expression by sterol-regulatory element binding protein-2.
2008,
Pubmed
Jia,
Enhanced circulating PCSK9 concentration by berberine through SREBP-2 pathway in high fat diet-fed rats.
2014,
Pubmed
Jick,
Comparison of prescription drug costs in the United States and the United Kingdom, Part 1: statins.
2012,
Pubmed
Jing,
Resveratrol downregulates PCSK9 expression and attenuates steatosis through estrogen receptor α-mediated pathway in L02 cells.
2019,
Pubmed
Johnston,
Potency of select statin drugs in a new mouse model of hyperlipidemia and atherosclerosis.
2001,
Pubmed
Katzmann,
PCSK9 Inhibition: Insights From Clinical Trials and Future Prospects.
2020,
Pubmed
Klein-Szanto,
Keep recycling going: New approaches to reduce LDL-C.
2019,
Pubmed
Lamb,
Inclisiran: First Approval.
2021,
Pubmed
Lee,
Antioxidative and anticancer activities of various ethanolic extract fractions from crown-of-thorns starfish (Acanthaster planci).
2014,
Pubmed
,
Echinobase
Libby,
Cholesterol and atherosclerosis.
2000,
Pubmed
Lusis,
Atherosclerosis.
2000,
Pubmed
Maron,
Cholesterol-lowering effect of a theaflavin-enriched green tea extract: a randomized controlled trial.
2003,
Pubmed
Mitsuya,
3'-Azido-3'-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro.
1985,
Pubmed
Mitsuya,
Strategies for antiviral therapy in AIDS.
NULL,
Pubmed
Nissen,
Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes.
2007,
Pubmed
Page,
PCSK9 inhibitors - mechanisms of action.
2016,
Pubmed
Pangestika,
Inhibitory effects of tangeretin and trans-ethyl caffeate on the HMG-CoA reductase activity: Potential agents for reducing cholesterol levels.
2020,
Pubmed
Paton,
PCSK9 inhibitors: monoclonal antibodies for the treatment of hypercholesterolemia.
2016,
Pubmed
Poznyak,
A brief overview of currently used atherosclerosis treatment approaches targeting lipid metabolism alterations.
2020,
Pubmed
Rady,
Primmorph extracts and mesohyls of marine sponges inhibit proliferation and migration of hepatocellular carcinoma cells in vitro.
2019,
Pubmed
Ravikumar,
Hepatoprotective and antioxidant activity of a mangrove plant Lumnitzera racemosa.
2011,
Pubmed
Rosenson,
Cholesterol-Lowering Agents.
2019,
Pubmed
Roth,
Global Burden of Cardiovascular Diseases and Risk Factors, 1990-2019: Update From the GBD 2019 Study.
2020,
Pubmed
Segatto,
Age- and sex-related differences in extra-hepatic low-density lipoprotein receptor.
2011,
Pubmed
Seidah,
The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation.
2003,
Pubmed
Seidah,
PCSK9: a key modulator of cardiovascular health.
2014,
Pubmed
Sirtori,
The pharmacology of statins.
2014,
Pubmed
Song,
Black Raspberry Extract Enhances LDL Uptake in HepG2 Cells by Suppressing PCSK9 Expression to Upregulate LDLR Expression.
2018,
Pubmed
Stone,
2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
2014,
Pubmed
Tai,
Curcumin enhances cell-surface LDLR level and promotes LDL uptake through downregulation of PCSK9 gene expression in HepG2 cells.
2014,
Pubmed
Tavori,
On the function and homeostasis of PCSK9: reciprocal interaction with LDLR and additional lipid effects.
2015,
Pubmed
Virmani,
Vulnerable plaque: the pathology of unstable coronary lesions.
2002,
Pubmed
Warden,
Inclisiran: A Novel Agent for Lowering Apolipoprotein B-containing Lipoproteins.
2021,
Pubmed
Yeo,
Anti-hyperlipidemic Effect of Polyphenol Extract (Seapolynol(™)) and Dieckol Isolated from Ecklonia cava in in vivo and in vitro Models.
2012,
Pubmed
Yoon,
Anti-hyperlipidemic effect of an edible brown algae, Ecklonia stolonifera, and its constituents on poloxamer 407-induced hyperlipidemic and cholesterol-fed rats.
2008,
Pubmed
Zhang,
Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation.
2007,
Pubmed