Caffeine blocks SREBP2-induced hepatic PCSK9 expression to enhance LDLR-mediated cholesterol clearance.
In: Nature Communications, Jg. 13 (2022-10-23), Heft 1, S. 1-17
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Zugriff:
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) Ca 2+ 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 Ca 2+ as a master regulator of cholesterol metabolism and identify a mechanism by which CF may protect against CVD. Caffeine may reduce cardiovascular disease risk, but the underlying mechanisms for these effects are incompletely understood. Here the authors report that caffeine inhibits the activation of the transcription factor SREBP2 to promote LDLc clearance through the PCSK9-LDLR axis. [ABSTRACT FROM AUTHOR]
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Titel: |
Caffeine blocks SREBP2-induced hepatic PCSK9 expression to enhance LDLR-mediated cholesterol clearance.
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Autor/in / Beteiligte Person: | Lebeau, Paul F. ; Byun, Jae Hyun ; Platko, Khrystyna ; Saliba, Paul ; Sguazzin, Matthew ; MacDonald, Melissa E. ; Paré, Guillaume ; Steinberg, Gregory R. ; Janssen, Luke J. ; Igdoura, Suleiman A. ; Tarnopolsky, Mark A. ; Wayne Chen, S. R. ; Seidah, Nabil G. ; Magolan, Jakob ; Austin, Richard C. |
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Zeitschrift: | Nature Communications, Jg. 13 (2022-10-23), Heft 1, S. 1-17 |
Veröffentlichung: | 2022 |
Medientyp: | academicJournal |
ISSN: | 2041-1723 (print) |
DOI: | 10.1038/s41467-022-28240-9 |
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