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Albert Salehi

S Albert Salehi

Research team manager

Albert Salehi

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

Author

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

Summary, in English

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.

Department/s

  • Islet cell physiology
  • EXODIAB: Excellence of Diabetes Research in Sweden

Publishing year

2022

Language

English

Pages

543-557

Publication/Series

Endocrine

Volume

76

Issue

3

Document type

Journal article

Publisher

Humana Press

Topic

  • Cardiac and Cardiovascular Systems

Keywords

  • HNF-1α
  • LDL-cholesterol
  • LDLR
  • Metformin
  • PCSK9
  • SREBP2

Status

Published

Research group

  • Islet cell physiology

ISBN/ISSN/Other

  • ISSN: 1355-008X