Funded in part by Amgen, Eli Lilly and Company, Sanofi, Novo Nordisk, Esperion Therapeutics, Amgen Canada
Caffeine blocks SREBP2-induced hepatic PCSK9 expression to enhance LDLR-mediated cholesterol clearance
Lebeau PF, Byun JH, Platko K, Saliba P, Sguazzin M, MacDonald ME, Paré G, Steinberg GR, Janssen LJ, Igdoura SA, Tarnopolsky MA, Wayne Chen SR, Seidah NG, Magolan J, Austin RC
Nature communications · 86 citations
Review labels
Neutral facts our review recorded about how this study was done. They describe method, never whether we like the result.
How it was studied
- Design
- In vitro/mechanistic study (classified by our AI screen)
- Studied in
- People, plus animal or lab work
- Main outcome
- Health markers and function
Who paid for it
- Funding
- Industry funded
- Company
- Amgen
- Company
- Eli Lilly and Company
- Company
- Sanofi
- Nonprofit
- Heart and Stroke Foundation of Canada
- University or hospital
- McMaster University
- Nonprofit
- Fondation Leducq
- Company
- Novo Nordisk
- Company
- Esperion Therapeutics
- Company
- Amgen Canada
- Government
- Canadian Institutes of Health Research
- Government
- CIHR
- Authors
- At least one author declares a financial tie to industry
- Grants
- Heart and Stroke Foundation of Canada (G-15–0009389); Canadian Institutes of Health Research (201709FDN‐CEBA‐116200); Fondation Leducq (#13CVD03); Heart and Stroke Foundation of Canada (G‐13‐0003064); Canadian Institutes of Health Research (FRN173520); Heart and Stroke Foundation of Canada (G-13-0003064 and G-15-00093889); Canadian Institutes of Health Research (G-15-0009389); Canadian Institutes of Health Research (148363); Amgen (201709FDN-CEBA-116200); Canadian Institutes of Health Research (G-13-0003064)
Based on 11 listed funder(s) and full-text disclosure statement.
Publication
- Published
- 2022-02-09 · Nat Commun · vol. 13 · issue 1 · p. 770
- Publisher
- Nature Portfolio
- Cited
- 118 citations · more than 100% of similar papers · 21.2× the field average
- Impact
- Top 10% most cited in its field
- References
- 61 works
- Access
- Open access (journal) · CC-BY
- Research areas
- Lipoproteins and Cardiovascular Health · Cholesterol and Lipid Metabolism · Nuclear Receptors and Signaling
- Keywords
- PCSK9, LDL receptor, Cholesterol, Caffeine, Chemistry, Cell biology, Biology, Biochemistry, Endocrinology, Lipoprotein
- MeSH
- liver, hepatocytes, animals, mice, inbred c57bl, humans, mice, caffeine, cholesterol, receptors, ldl, male, lipid metabolism, sterol regulatory element binding protein 2, cholesterol, ldl, hep g2 cells, proprotein convertase 9
15 authors
From CA
- Paul F. LebeauSt. Joseph’s Healthcare Hamilton; McMaster University
- Jae Hyun ByunSt. Joseph’s Healthcare Hamilton; McMaster University
- Khrystyna PlatkoSt. Joseph’s Healthcare Hamilton; McMaster University
- Paul SalibaMcMaster University
- Matthew A. SguazzinMcMaster University
- Melissa E. MacDonaldSt. Joseph’s Healthcare Hamilton; McMaster University
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.
Abstract via Europe PMC. Copyright remains with the authors or publisher (CC BY).
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