Acaudina molpadioides mediates lipid uptake by suppressing PCSK9 transcription and increasing LDL receptor in human liver cells

Acaudina molpadioides has been long used as traditional medicinal resources and reported to demonstrate various important bioactivities such as anticoagulation, antithrombosis, anti-hyperglycemia and anticancer. However, its lipid lowering activity is yet to be fully explored. Proprotein convertase...

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Autores principales:	Allicia Jack, Muzaida Aminah Mohd, Nurjannatul Naim Kamaruddin, Lukman Hakim Mohd Din, Nor Azwin Hajri, Tengku Sifzizul Tengku Muhammad
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Atherosclerosis Low density lipoprotein Promoter-reporter based assay PCSK9 Acaudina molpadioides Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/d0c23ba7fce54eef9c4cd710757fe32a
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spelling	oai:doaj.org-article:d0c23ba7fce54eef9c4cd710757fe32a2021-11-20T04:56:44ZAcaudina molpadioides mediates lipid uptake by suppressing PCSK9 transcription and increasing LDL receptor in human liver cells1319-562X10.1016/j.sjbs.2021.08.003https://doaj.org/article/d0c23ba7fce54eef9c4cd710757fe32a2021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S1319562X21006768https://doaj.org/toc/1319-562XAcaudina molpadioides has been long used as traditional medicinal resources and reported to demonstrate various important bioactivities such as anticoagulation, antithrombosis, anti-hyperglycemia and anticancer. However, its lipid lowering activity is yet to be fully explored. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme that enhances the lysosomal degradation of hepatic low density lipoprotein receptor (LDLR) resulting in excessive accumulation of the plasma levels of LDL-cholesterols (LDL-C) which subsequently accelerate atherosclerosis. In the present study, A. molpadioides fractions were subjected to promoter-reporter luciferase assay to determine its role as PCSK9 inhibitors. It was found both fractions (EFA and EFB) reduced the transcriptional activity of PCSK9 promoter. Among the seven 5′end deletion constructs of PCSK9 promoter, fragments D1 (−1,711/−94), D3 (−709/−94) and D4 (−440/−94), were suppressed in the presence of both fractions whereas D2 (−1,214/−94), and, D6 (−351/−94) as well as D7 (−335/−94) were inhibited only by EFA and EFB, respectively. Further transcription factor binding sites prediction using MatInspector software discovered various potential cis-regulatory elements namely, PPAR, KLFs, RBPJ-kappa and SREBP that may potentially be involved in ameliorating the transcriptional activity of PCSK9. Immunofluorescence staining was used to evaluate the effects of both fractions on LDL-C and LDLR. Results showed that levels of LDL-C uptake in EFA-treated cells were 69.1% followed by EFB at 32.6%, as compared to untreated control after 24 h treatment. The LDLR protein distribution was induced by 62.41% and 32.2%, which corresponded to an increase in LDL-C uptake in both EFA and EFB treatment, respectively. Hence, the inhibition of PCSK9 by bioactive compounds in EFA and EFB could be another promising therapeutic agent in reducing the cholesterol levels and atherosclerosis by targeting PCSK9.Allicia JackMuzaida Aminah MohdNurjannatul Naim KamaruddinLukman Hakim Mohd DinNor Azwin HajriTengku Sifzizul Tengku MuhammadElsevierarticleAtherosclerosisLow density lipoproteinPromoter-reporter based assayPCSK9Acaudina molpadioidesBiology (General)QH301-705.5ENSaudi Journal of Biological Sciences, Vol 28, Iss 12, Pp 7105-7116 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Atherosclerosis Low density lipoprotein Promoter-reporter based assay PCSK9 Acaudina molpadioides Biology (General) QH301-705.5
spellingShingle	Atherosclerosis Low density lipoprotein Promoter-reporter based assay PCSK9 Acaudina molpadioides Biology (General) QH301-705.5 Allicia Jack Muzaida Aminah Mohd Nurjannatul Naim Kamaruddin Lukman Hakim Mohd Din Nor Azwin Hajri Tengku Sifzizul Tengku Muhammad Acaudina molpadioides mediates lipid uptake by suppressing PCSK9 transcription and increasing LDL receptor in human liver cells
description	Acaudina molpadioides has been long used as traditional medicinal resources and reported to demonstrate various important bioactivities such as anticoagulation, antithrombosis, anti-hyperglycemia and anticancer. However, its lipid lowering activity is yet to be fully explored. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme that enhances the lysosomal degradation of hepatic low density lipoprotein receptor (LDLR) resulting in excessive accumulation of the plasma levels of LDL-cholesterols (LDL-C) which subsequently accelerate atherosclerosis. In the present study, A. molpadioides fractions were subjected to promoter-reporter luciferase assay to determine its role as PCSK9 inhibitors. It was found both fractions (EFA and EFB) reduced the transcriptional activity of PCSK9 promoter. Among the seven 5′end deletion constructs of PCSK9 promoter, fragments D1 (−1,711/−94), D3 (−709/−94) and D4 (−440/−94), were suppressed in the presence of both fractions whereas D2 (−1,214/−94), and, D6 (−351/−94) as well as D7 (−335/−94) were inhibited only by EFA and EFB, respectively. Further transcription factor binding sites prediction using MatInspector software discovered various potential cis-regulatory elements namely, PPAR, KLFs, RBPJ-kappa and SREBP that may potentially be involved in ameliorating the transcriptional activity of PCSK9. Immunofluorescence staining was used to evaluate the effects of both fractions on LDL-C and LDLR. Results showed that levels of LDL-C uptake in EFA-treated cells were 69.1% followed by EFB at 32.6%, as compared to untreated control after 24 h treatment. The LDLR protein distribution was induced by 62.41% and 32.2%, which corresponded to an increase in LDL-C uptake in both EFA and EFB treatment, respectively. Hence, the inhibition of PCSK9 by bioactive compounds in EFA and EFB could be another promising therapeutic agent in reducing the cholesterol levels and atherosclerosis by targeting PCSK9.
format	article
author	Allicia Jack Muzaida Aminah Mohd Nurjannatul Naim Kamaruddin Lukman Hakim Mohd Din Nor Azwin Hajri Tengku Sifzizul Tengku Muhammad
author_facet	Allicia Jack Muzaida Aminah Mohd Nurjannatul Naim Kamaruddin Lukman Hakim Mohd Din Nor Azwin Hajri Tengku Sifzizul Tengku Muhammad
author_sort	Allicia Jack
title	Acaudina molpadioides mediates lipid uptake by suppressing PCSK9 transcription and increasing LDL receptor in human liver cells
title_short	Acaudina molpadioides mediates lipid uptake by suppressing PCSK9 transcription and increasing LDL receptor in human liver cells
title_full	Acaudina molpadioides mediates lipid uptake by suppressing PCSK9 transcription and increasing LDL receptor in human liver cells
title_fullStr	Acaudina molpadioides mediates lipid uptake by suppressing PCSK9 transcription and increasing LDL receptor in human liver cells
title_full_unstemmed	Acaudina molpadioides mediates lipid uptake by suppressing PCSK9 transcription and increasing LDL receptor in human liver cells
title_sort	acaudina molpadioides mediates lipid uptake by suppressing pcsk9 transcription and increasing ldl receptor in human liver cells
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/d0c23ba7fce54eef9c4cd710757fe32a
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Acaudina molpadioides mediates lipid uptake by suppressing PCSK9 transcription and increasing LDL receptor in human liver cells

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