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02-03-2022 | Metformin | Original Article

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

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

Published in: Endocrine | Issue 3/2022

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.

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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
Authors: Amjad Ali
Hema Unnikannan
Jasmin Shafarin
Khuloud Bajbouj
Jalal Taneera
Jibran Sualeh Muhammad
Haydar Hasan
Albert Salehi
Samir Awadallah
Mawieh Hamad
Publication date: 02-03-2022
Publisher: Springer US
Keyword: Metformin
Published in: Endocrine / Issue 3/2022
Print ISSN: 1355-008X
Electronic ISSN: 1559-0100
DOI: https://doi.org/10.1007/s12020-022-03022-x

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Keynote webinar | Spotlight on medication adherence

Springer Medicine

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Other articles of this Issue 3/2022

Body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR) e waist body mass index (wBMI): Which is better?

Reply to Editors—Effect of high dose vitamin D supplementation on indices of sarcopenia and obesity assessed by DXA among older adults: a randomized controlled trial

Components of IGF-axis in growth disorders: a systematic review and patent landscape report

Assessment of circulating fibrotic proteins (periostin and tenascin -C) In Type 2 diabetes mellitus patients with and without retinopathy

Prognostic significance of laterality in lung neuroendocrine tumors

Natural history, predictive factors of apparent disease (structural or biochemical) and spontaneous excellent response in patients with papillary thyroid carcinoma and indeterminate response to initial therapy with radioiodine

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