Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein that serves as a major regulator of low-density lipoprotein cholesterol (LDL-C) levels in the bloodstream. Elevated LDL-C, often called “bad cholesterol,” is a significant risk factor for cardiovascular disease. The discovery of PCSK9 illuminated a new pathway for cholesterol regulation, moving beyond traditional dietary and pharmaceutical approaches. Inhibition of PCSK9 activity, essentially blocking the enzyme’s function, lowers circulating LDL-C. This has led to the development of powerful injectable medications, but it has also spurred interest in finding natural ways to modulate this protein. Research is actively exploring how dietary compounds and lifestyle adjustments may offer a complementary approach to managing PCSK9 activity.
Understanding the PCSK9 Mechanism
The biological function of the PCSK9 protein is to control the number of LDL receptors (LDLR) present on the surface of liver cells, or hepatocytes. These LDLRs are responsible for clearing LDL cholesterol from the circulation by binding to it and internalizing the resulting complex. Once inside the cell, the LDL particle is broken down, and the LDLR is typically recycled back to the cell surface to capture more LDL cholesterol.
PCSK9 disrupts this recycling process by acting as a molecular chaperone for the receptor. Once secreted by the liver, PCSK9 binds to the LDLR on the cell surface, and this complex is then internalized by the hepatocyte. Unlike a normal LDL-LDLR complex, the presence of PCSK9 prevents the receptor from separating in the acidic environment of the endosome.
The PCSK9-bound receptor is instead rerouted away from the recycling pathway and directed toward the lysosome, which is the cell’s degradation center. Degradation of the LDLR means fewer receptors are available on the liver cell surface to remove LDL cholesterol from the blood. Consequently, higher levels of circulating PCSK9 lead to a reduction in LDL receptor density, which results in elevated plasma levels of LDL-C. Inhibition of PCSK9 is desirable because it allows more LDLRs to return to the surface, thus enhancing the liver’s ability to clear “bad cholesterol” from the bloodstream.
Dietary Sources of Natural Inhibitors
Research into natural compounds has identified several phytochemicals that exhibit PCSK9-inhibitory effects. These compounds are frequently found in common foods and medicinal plants. The effects observed in these studies, which are often preclinical, suggest a potential for dietary modulation of PCSK9.
Berberine and Alkaloids
Berberine, an isoquinoline alkaloid found in plants like European barberry and goldenseal, is one of the most studied natural PCSK9 inhibitors. It has demonstrated the ability to lower PCSK9 expression by acting on gene transcription. Specifically, berberine promotes the degradation of hepatocyte nuclear factor 1 alpha (HNF1\(\alpha\)), which is a transcription factor that regulates the expression of the PCSK9 gene. By downregulating HNF1\(\alpha\), berberine reduces the amount of PCSK9 messenger RNA (mRNA) produced, which ultimately leads to lower circulating PCSK9 levels.
Polyphenols and Flavonoids
A wide variety of polyphenolic compounds, which are abundant in fruits, vegetables, tea, and wine, have been investigated for their effects on PCSK9.
Key Polyphenols and Flavonoids
- Quercetin: This flavonoid, present in apples, onions, and berries, reduces PCSK9 mRNA levels in liver cells. Its proposed mechanism involves regulating the protein sortilin, which is involved in PCSK9 secretion.
- Resveratrol: Found in the skin of grapes and red wine, this polyphenol reduces PCSK9 expression and promotes LDL uptake in laboratory settings.
- Epigallocatechin gallate (EGCG): Rich in green tea extract, EGCG appears to affect the protein’s secretion from liver cells, reducing the amount of PCSK9 that enters the bloodstream.
- Curcumin: The main active component of turmeric, curcumin reduces PCSK9 gene expression by inhibiting the activity of the nuclear transcription factor HNF1\(\alpha\).
- Lycopene: This red pigment, found in tomatoes, is also reported to suppress PCSK9 expression in the liver.
Omega Fatty Acids and Phytosterols
Omega-3 polyunsaturated fatty acids (PUFAs), commonly found in fatty fish like salmon and mackerel, have been associated with reduced levels of circulating PCSK9. Long-term dietary intake of omega-3-rich sources is thought to modulate PCSK9 levels. Phytosterols and stanols, which are plant compounds structurally similar to cholesterol, are widely used as dietary supplements to reduce cholesterol absorption. They have also been noted for their ability to influence PCSK9, though the exact nature of this interaction is still under investigation. The potency of these natural compounds is generally lower than that of pharmaceutical inhibitors, and current research is primarily focused on cellular or animal models.
Lifestyle Modifiers and PCSK9 Activity
Systemic factors influenced by lifestyle choices can regulate the overall production of the PCSK9 enzyme. This regulation involves metabolic pathways that control gene expression, offering a distinct and complementary approach to modulation.
Regular physical exercise has been suggested to act as a negative modulator of PCSK9 plasma levels. Exercise improves overall metabolic status, including enhanced insulin sensitivity. This is relevant because higher insulin levels are associated with increased PCSK9 expression. Exercise may also reduce levels of certain inflammatory markers, such as resistin, which are known to increase PCSK9 expression in liver cells.
Weight management is also a factor, particularly in relation to visceral fat, which contributes to chronic low-grade inflammation. This inflammatory state is linked to increased PCSK9 transcription. Reducing excess body fat can therefore indirectly lower the systemic drivers that promote PCSK9 production.
Sleep and the body’s internal circadian clock also play a role in regulating PCSK9 levels. Circulating PCSK9 follows a strong circadian rhythm, naturally peaking in the mid-morning. Disruptions to the normal sleep-wake cycle, such as shift work, could interfere with the physiological regulation of cholesterol homeostasis.