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

Ali, Amjad ; Unnikannan, Hema ; Shafarin, Jasmin ; Bajbouj, Khuloud ; Taneera, Jalal ; Muhammad, Jibran Sualeh ; Hasan, Haydar ; Salehi, Albert LU orcid ; Awadallah, Samir and Hamad, Mawieh (2022) In Endocrine 76(3). p.543-557
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... (More)

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.

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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
HNF-1α, LDL-cholesterol, LDLR, Metformin, PCSK9, SREBP2
in
Endocrine
volume
76
issue
3
pages
543 - 557
publisher
Humana Press
external identifiers
  • scopus:85125534539
  • pmid:35237909
ISSN
1355-008X
DOI
10.1007/s12020-022-03022-x
language
English
LU publication?
yes
id
6b1c8563-bb85-4c77-aa87-7d08a317245e
date added to LUP
2022-04-19 15:04:25
date last changed
2025-01-13 16:07:12
@article{6b1c8563-bb85-4c77-aa87-7d08a317245e,
  abstract     = {{<p>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.</p>}},
  author       = {{Ali, Amjad and Unnikannan, Hema and Shafarin, Jasmin and Bajbouj, Khuloud and Taneera, Jalal and Muhammad, Jibran Sualeh and Hasan, Haydar and Salehi, Albert and Awadallah, Samir and Hamad, Mawieh}},
  issn         = {{1355-008X}},
  keywords     = {{HNF-1α; LDL-cholesterol; LDLR; Metformin; PCSK9; SREBP2}},
  language     = {{eng}},
  number       = {{3}},
  pages        = {{543--557}},
  publisher    = {{Humana Press}},
  series       = {{Endocrine}},
  title        = {{Metformin enhances LDL-cholesterol uptake by suppressing the expression of the pro-protein convertase subtilisin/kexin type 9 (PCSK9) in liver cells}},
  url          = {{http://dx.doi.org/10.1007/s12020-022-03022-x}},
  doi          = {{10.1007/s12020-022-03022-x}},
  volume       = {{76}},
  year         = {{2022}},
}