Flavonoids regulate LDLR through different mechanisms tied to their specific structures

Katrine Bjune; Pia Skovholt Halvorsen; Helle Wangensteen; Trond P Leren; Martin Prøven Bogsrud; Thea Bismo Strøm

doi:10.1016/j.jlr.2024.100539

Flavonoids regulate LDLR through different mechanisms tied to their specific structures

J Lipid Res. 2024 Mar 29;65(5):100539. doi: 10.1016/j.jlr.2024.100539. Online ahead of print.

Authors

Katrine Bjune¹, Pia Skovholt Halvorsen², Helle Wangensteen³, Trond P Leren², Martin Prøven Bogsrud², Thea Bismo Strøm²

Affiliations

¹ Unit for Cardiac and Cardiovascular Genetics, Department of Medical Genetics, Oslo University Hospital, Oslo, Norway. Electronic address: kabjun@ous-hf.no.
² Unit for Cardiac and Cardiovascular Genetics, Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
³ Section for Pharmaceutical Chemistry, Department of Pharmacy, University of Oslo, Oslo, Norway.

Abstract

Flavonoids, polyphenolic compounds found in plant-based diets, are associated with reduced risk of cardiovascular disease and longevity. These components are reported to reduce plasma levels of low-density lipoprotein (LDL) through an upregulation of the LDL receptor (LDLR), but the mechanism is still largely unknown. In this study, we have systematically screened the effect of 12 flavonoids from six different flavonoid subclasses on the effect on LDLR. This paper provides an in-depth analysis on how these flavonoids affect LDLR regulation and functionality. We found that most but not all of the tested flavonoids increased LDLR mRNA levels. Surprisingly, this increase was attributed to different regulatory mechanisms, such as enhanced LDLR promoter activity, LDLR mRNA stabilization, or LDLR protein stabilization, of which specific effectual parts of the flavonoid molecular structure could be assigned. These types of comparative analysis of various flavonoids enhance clarity and deepen the understanding of how the different structures of flavonoids affect LDLR regulation. Our data offer useful insights that may guide future research in developing therapeutic approaches for cardiovascular health.

Keywords: antioxidants; atherosclerosis; cardiovascular disease; lipoproteins; metabolism; nutrition; polyphenols; structure.