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Novel caffeine derivatives mitigate hyperlipidemia by reducing PCSK9 expression and secretion

Background and Aims: Accumulating evidence suggests that caffeine, one of the most highly consumed naturally occurring drugs in modern society, reduces cardiovascular disease (CVD) risk. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an established circulating factor that regulates low density lipoprotein cholesterol (LDLc) by binding to and targeting the LDL receptor (LDLR) for degradation. We have recently reported that caffeine increases endoplasmic reticulum (ER) Ca2+ levels in hepatocytes to block the activation of the transcription factors that drive PCSK9 expression, namely the sterol regulatory element-binding proteins (SREBPs). As a result, increased ER Ca2+ levels cause binding of the SREBPs to the molecular chaperone GRP78, thereby retaining the SREBPs in the ER and mitigating their activity. The overall aim of this study is to develop novel caffeine derivatives with increased potency against PCSK9 expression/secretion.


Methods: The immortalized human hepatocyte cell line HuH7, known to express and secrete PCSK9, were treated with caffeine or our novel caffeine derivatives to assess their ability to maintain/increase ER Ca2+ levels while reducing PCSK expression/secretion using ELISAs. Mice were then treated with our lead caffeine derivatives to assess their ability to reduce blood levels of PCSK9 and LDLc.


Results: Of the >200 novel caffeine derivatives developed, >60 derivatives showed superior efficacy in lowering PCSK9 and enhancing ER Ca2+, relative to caffeine. Our three lead derivatives (1818, 2137 and 2146) were >1000-fold more potent than caffeine at increasing ER Ca2+ levels while reducing PCSK9 secretion in HuH7 cells. Consistent with these findings, the concentrations of 2146 were significantly lower that caffeine to achieve similar reductions in blood PCSK9 levels (1 mg/kg versus 25 mg/kg). However, only caffeine enhanced locomotor activity due to CNS activation.


Conclusions: We have developed novel caffeine derivatives that markedly reduce PCSK9 expression/secretion in cultured hepatocytes and in mice, which represent an orally active, cost-effect therapeutic for the management of hyperlipidemia.




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