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

 But is it caffeine or the other compounds in coffee?

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 &
• Richard C. Austin 

Nature Communications volume 13, Article number: 770 (2022) Cite this article

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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.

Introduction

Increased levels of circulating low-density lipoprotein cholesterol (LDLc) are tightly linked to the development of cardiovascular disease (CVD). Despite the approval of several therapies that lower LDLc, many patients fail to reach their LDL lowering goal due to intolerance, adverse events, or simply the high cost of medications. An important regulator of LDLc is the sterol regulatory element-binding protein 2 (SREBP2), which is an endoplasmic reticulum (ER)-resident transcription factor. SREBP2 is activated by reductions in intracellular cholesterol and loss of ER Ca²⁺, which then triggers translocation to the nucleus and the induction of cholesterol regulatory genes including the proprotein convertase subtilisin/kexin type 9 (PCSK9), the low-density lipoprotein receptor (LDLR), and HMG-CoA reductase (HMGR)¹. Recent advancements in therapies available for the management of dyslipidemia and CVD have led to the characterization of PCSK9 as a hepatocyte-secreted circulating factor capable of enhancing the degradation of cell-surface LDLR^2,3,4,5. By extension, PCSK9 also reduces the ability of metabolically active tissues, such as the liver, to remove excess LDLc from the blood. Based on these seminal discoveries, anti-PCSK9 antibodies are now available to patients at high risk of CVD, yielding an unprecedented 60–70% reduction of LDLc levels⁶. Although efficacious, the high cost and/or need for subcutaneous administration of anti-PCSK9 antibodies poses a limit to their availability to patients worldwide⁷. Such circumstances warrant the need for additional studies examining the molecular mechanisms that modulate the expression and secretion of PCSK9 from hepatocytes in order to develop more cost-effective therapies.

Caffeine (CF) or 1,3,7 trimethylxanthine, is best known as a stimulant alkaloid of the central nervous system found in various plants and is commonly found in coffee and tea. The majority of published literature demonstrates that the average adult habitual caffeine drinker consumes between 400 and 600 mg of CF daily and organizations like Health Canada and the Food and Drug Administration conclude that such doses are not negatively associated with toxicity, cardiovascular effects, bone status, calcium imbalance, behavior, the incidence of cancer or effects on male fertility⁸. On the contrary, accumulating evidence now suggests that moderate to high levels of CF (>600 mg), consumed daily in the form of non-alcoholic beverages, are associated with a reduction in CVD risk^8,9. Although biochemical studies have shown that CF increases intracellular Ca²⁺ levels and induces vasodilation of the vascular endothelium via release of nitric oxide^10,11, a cellular process known to be cardioprotective¹², molecular mechanisms supporting clinical evidence are currently lacking.

In the current study, we demonstrate that clinically relevant concentrations of caffeine suppress SREBP2 transcriptional activation in liver hepatocytes, thereby leading to a reduction of PCSK9 in both mice and humans. Using structure/activity relationships (SAR), we have also generated several xanthine derivatives with heightened antagonism against SREBP2 and PCSK9, compared to CF. Overall, these studies characterize the mechanism by which CF impacts the expression of genes well-known to mediate CVD risk.

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