Caffeine blocks SREBP2-induced hepatic PCSK9 expression to enhance LDLR-mediated cholesterol clearance

Paul F. Lebeau, Jae Hyun Byun, Khrystyna Platko, Paul Saliba, Matthew Sguazzin, Melissa E. MacDonald, Guillaume Paré, Gregory R. Steinberg, Luke J. Janssen, Suleiman A. Igdoura, Mark A. Tarnopolsky, S. R. Wayne Chen, Nabil G. Seidah, Jakob Magolan and Richard C. Austin ()
Additional contact information
Paul F. Lebeau: McMaster University, The Research Institute of St. Joe’s Hamilton and the Hamilton Center for Kidney Research
Jae Hyun Byun: McMaster University, The Research Institute of St. Joe’s Hamilton and the Hamilton Center for Kidney Research
Khrystyna Platko: McMaster University, The Research Institute of St. Joe’s Hamilton and the Hamilton Center for Kidney Research
Paul Saliba: McMaster University
Matthew Sguazzin: McMaster University
Melissa E. MacDonald: McMaster University, The Research Institute of St. Joe’s Hamilton and the Hamilton Center for Kidney Research
Guillaume Paré: McMaster University
Gregory R. Steinberg: McMaster University
Luke J. Janssen: St. Joseph’s Hospital
Suleiman A. Igdoura: McMaster University
Mark A. Tarnopolsky: McMaster University
S. R. Wayne Chen: University of Calgary
Nabil G. Seidah: affiliated to the University of Montreal
Jakob Magolan: McMaster University
Richard C. Austin: McMaster University, The Research Institute of St. Joe’s Hamilton and the Hamilton Center for Kidney Research

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Evidence suggests that caffeine (CF) reduces cardiovascular disease (CVD) risk. However, the mechanism by which this occurs has not yet been uncovered. Here, we investigated the effect of CF on the expression of two bona fide regulators of circulating low-density lipoprotein cholesterol (LDLc) levels; the proprotein convertase subtilisin/kexin type 9 (PCSK9) and the low-density lipoprotein receptor (LDLR). Following the observation that CF reduced circulating PCSK9 levels and increased hepatic LDLR expression, additional CF-derived analogs with increased potency for PCSK9 inhibition compared to CF itself were developed. The PCSK9-lowering effect of CF was subsequently confirmed in a cohort of healthy volunteers. Mechanistically, we demonstrate that CF increases hepatic endoplasmic reticulum (ER) Ca2+ levels to block transcriptional activation of the sterol regulatory element-binding protein 2 (SREBP2) responsible for the regulation of PCSK9, thereby increasing the expression of the LDLR and clearance of LDLc. Our findings highlight ER Ca2+ as a master regulator of cholesterol metabolism and identify a mechanism by which CF may protect against CVD.

Date: 2022
References: View complete reference list from CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-022-28240-9 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28240-9

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-28240-9

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().