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. 2022 Jun;76(3):543-557.
doi: 10.1007/s12020-022-03022-x. Epub 2022 Mar 2.

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

Amjad Ali  1 , Hema Unnikannan  1 , Jasmin Shafarin  1 , Khuloud Bajbouj  1   2 , Jalal Taneera  1   2 , Jibran Sualeh Muhammad  1   2 , Haydar Hasan  3 , Albert Salehi  4   5 , Samir Awadallah  6   7 , Mawieh Hamad  8   9
Affiliations

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

Amjad Ali et al. Endocrine. 2022 Jun.

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.

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