Metformin enhances LDL-cholesterol uptake by suppressing the expression of the pro-protein convertase subtilisin/kexin type 9 (PCSK9) in liver cells

Amjad Ali; Hema Unnikannan; Jasmin Shafarin; Khuloud Bajbouj; Jalal Taneera; Jibran Sualeh Muhammad; Haydar Hasan; Albert Salehi; Samir Awadallah; Mawieh Hamad

doi:10.1007/s12020-022-03022-x

Metformin enhances LDL-cholesterol uptake by suppressing the expression of the pro-protein convertase subtilisin/kexin type 9 (PCSK9) in liver cells

Amjad Ali, Hema Unnikannan, Jasmin Shafarin, Khuloud Bajbouj, Jalal Taneera, Jibran Sualeh Muhammad, Haydar Hasan, Albert Salehi, Samir Awadallah^*, Mawieh Hamad^*

^*Corresponding author for this work

Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

Abstract

Purpose: Metformin (MF) intake associates with reduced levels of circulating low-density lipoprotein-cholesterol (LDL-C). This has been attributed to the activation of AMPK, which differentially regulates the expression of multiple genes involved in cholesterol synthesis and trafficking. However, the exact mechanism underlying the LDL-C lowering effect of MF remains ambiguous.

Methods: MF-treated Hep-G2 and HuH7 cells were evaluated for cell viability and the expression status of key lipid metabolism-related genes along with LDL-C uptake efficiency.

Results: MF treatment resulted in decreased expression and secretion of PCSK9, increased expression of LDLR and enhanced LDL-C uptake in hepatocytes. It also resulted in increased expression of activated AMPK (p-AMPK) and decreased expression of SREBP2 and HNF-1α proteins. Transcriptomic analysis of MF-treated Hep-G2 cells confirmed these findings and showed that other key lipid metabolism-related genes including those that encode apolipoproteins (APOB, APOC2, APOC3 and APOE), MTTP and LIPC are downregulated. Lastly, MF treatment associated with reduced HMG-CoA reductase expression and activity.

Conclusions: These findings suggest that MF treatment reduces circulating LDL-C levels by suppressing PCSK9 expression and enhancing LDLR expression; hence the potential therapeutic utility of MF in hypercholesterolemia.

Original language	English
Pages (from-to)	543-557
Number of pages	15
Journal	Endocrine
Volume	76
Issue number	3
Early online date	2 Mar 2022
DOIs	https://doi.org/10.1007/s12020-022-03022-x
Publication status	Published - Jun 2022

Bibliographical note

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Keywords

HNF-1α
LDL-cholesterol
LDLR
Metformin
PCSK9
SREBP2

ASJC Scopus subject areas

Endocrinology, Diabetes and Metabolism
Endocrinology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1007/s12020-022-03022-x

Cite this

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title = "Metformin enhances LDL-cholesterol uptake by suppressing the expression of the pro-protein convertase subtilisin/kexin type 9 (PCSK9) in liver cells",

abstract = "Purpose: Metformin (MF) intake associates with reduced levels of circulating low-density lipoprotein-cholesterol (LDL-C). This has been attributed to the activation of AMPK, which differentially regulates the expression of multiple genes involved in cholesterol synthesis and trafficking. However, the exact mechanism underlying the LDL-C lowering effect of MF remains ambiguous. Methods: MF-treated Hep-G2 and HuH7 cells were evaluated for cell viability and the expression status of key lipid metabolism-related genes along with LDL-C uptake efficiency. Results: MF treatment resulted in decreased expression and secretion of PCSK9, increased expression of LDLR and enhanced LDL-C uptake in hepatocytes. It also resulted in increased expression of activated AMPK (p-AMPK) and decreased expression of SREBP2 and HNF-1α proteins. Transcriptomic analysis of MF-treated Hep-G2 cells confirmed these findings and showed that other key lipid metabolism-related genes including those that encode apolipoproteins (APOB, APOC2, APOC3 and APOE), MTTP and LIPC are downregulated. Lastly, MF treatment associated with reduced HMG-CoA reductase expression and activity. Conclusions: These findings suggest that MF treatment reduces circulating LDL-C levels by suppressing PCSK9 expression and enhancing LDLR expression; hence the potential therapeutic utility of MF in hypercholesterolemia.",

keywords = "HNF-1α, LDL-cholesterol, LDLR, Metformin, PCSK9, SREBP2",

author = "Amjad Ali and Hema Unnikannan and Jasmin Shafarin and Khuloud Bajbouj and Jalal Taneera and Muhammad, \{Jibran Sualeh\} and Haydar Hasan and Albert Salehi and Samir Awadallah and Mawieh Hamad",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.",

year = "2022",

month = jun,

doi = "10.1007/s12020-022-03022-x",

language = "English",

volume = "76",

pages = "543--557",

journal = "Endocrine",

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TY - JOUR

T1 - Metformin enhances LDL-cholesterol uptake by suppressing the expression of the pro-protein convertase subtilisin/kexin type 9 (PCSK9) in liver cells

AU - Ali, Amjad

AU - Unnikannan, Hema

AU - Shafarin, Jasmin

AU - Bajbouj, Khuloud

AU - Taneera, Jalal

AU - Muhammad, Jibran Sualeh

AU - Hasan, Haydar

AU - Salehi, Albert

AU - Awadallah, Samir

AU - Hamad, Mawieh

PY - 2022/6

Y1 - 2022/6

N2 - Purpose: Metformin (MF) intake associates with reduced levels of circulating low-density lipoprotein-cholesterol (LDL-C). This has been attributed to the activation of AMPK, which differentially regulates the expression of multiple genes involved in cholesterol synthesis and trafficking. However, the exact mechanism underlying the LDL-C lowering effect of MF remains ambiguous. Methods: MF-treated Hep-G2 and HuH7 cells were evaluated for cell viability and the expression status of key lipid metabolism-related genes along with LDL-C uptake efficiency. Results: MF treatment resulted in decreased expression and secretion of PCSK9, increased expression of LDLR and enhanced LDL-C uptake in hepatocytes. It also resulted in increased expression of activated AMPK (p-AMPK) and decreased expression of SREBP2 and HNF-1α proteins. Transcriptomic analysis of MF-treated Hep-G2 cells confirmed these findings and showed that other key lipid metabolism-related genes including those that encode apolipoproteins (APOB, APOC2, APOC3 and APOE), MTTP and LIPC are downregulated. Lastly, MF treatment associated with reduced HMG-CoA reductase expression and activity. Conclusions: These findings suggest that MF treatment reduces circulating LDL-C levels by suppressing PCSK9 expression and enhancing LDLR expression; hence the potential therapeutic utility of MF in hypercholesterolemia.

AB - Purpose: Metformin (MF) intake associates with reduced levels of circulating low-density lipoprotein-cholesterol (LDL-C). This has been attributed to the activation of AMPK, which differentially regulates the expression of multiple genes involved in cholesterol synthesis and trafficking. However, the exact mechanism underlying the LDL-C lowering effect of MF remains ambiguous. Methods: MF-treated Hep-G2 and HuH7 cells were evaluated for cell viability and the expression status of key lipid metabolism-related genes along with LDL-C uptake efficiency. Results: MF treatment resulted in decreased expression and secretion of PCSK9, increased expression of LDLR and enhanced LDL-C uptake in hepatocytes. It also resulted in increased expression of activated AMPK (p-AMPK) and decreased expression of SREBP2 and HNF-1α proteins. Transcriptomic analysis of MF-treated Hep-G2 cells confirmed these findings and showed that other key lipid metabolism-related genes including those that encode apolipoproteins (APOB, APOC2, APOC3 and APOE), MTTP and LIPC are downregulated. Lastly, MF treatment associated with reduced HMG-CoA reductase expression and activity. Conclusions: These findings suggest that MF treatment reduces circulating LDL-C levels by suppressing PCSK9 expression and enhancing LDLR expression; hence the potential therapeutic utility of MF in hypercholesterolemia.

KW - HNF-1α

KW - LDL-cholesterol

KW - LDLR

KW - Metformin

KW - PCSK9

KW - SREBP2

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SN - 1355-008X

VL - 76

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EP - 557

JO - Endocrine

JF - Endocrine

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ER -

Metformin enhances LDL-cholesterol uptake by suppressing the expression of the pro-protein convertase subtilisin/kexin type 9 (PCSK9) in liver cells

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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