After water, coffee is the most highly consumed drink worldwide. This popular beverage has ancient historical roots, dating back to 700AD and originating from the mountainous regions of Ethiopia. It is deeply ingrained into many cultures across the globe, and its highly preserved methods of preparation filter down from ancient rituals.

But is it good for our health? Previous research exploring the nutrient profile of coffee demonstrate its high polyphenol content. These are powerful anti-inflammatory and antioxidative components which are linked to protection against cell damage and lowering inflammation.

Further research shows how coffee exhibits protective effects and is linked to reducing the risk of certain age-related diseases, such as dementia, metabolic disease and cardiovascular disease.

A study published in the Open access journal Nutrients by researchers from the USA investigates how components such as polyphenols in coffee exhibit health protective effects. Specifically, the researchers tested to see if the various polyphenols in brewed coffee bind to a key receptor involved in regulating stress, called the Orphan Nuclear Receptor 4A1.

Orphan Nuclear Receptor 4A1 is health protective

The orphan nuclear receptor 4A1 (NR4A1) is a receptor involved in regulating cellular stress responses. It acts as a key transcription factor by regulating expression of genes involved in immune and inflammatory pathways. It also plays a role in signalling pathways associated with cytokines and growth factors such as transforming growth factor beta.

Its mechanism of action is not fully clear, but experiments in mice where the gene is inactivated, known as knockout experiments, show heightened cellular damage and tissue injury. The research to date confirms its role in processes such as wound healing, tissue repair, and stress-induced damages associated with ageing.

The receptor’s astounding versatility shows how it acts as both an anti-apoptotic – the key process by which programmed cell death occurs –  and a pro-apoptotic regulator, depending on its position and context within the cell.

Previous studies show that although the gene is involved in regulating homeostasis in healthy cells, its overexpression is also demonstrated in transformed cancer cells, linking the gene to cancer progression. Previous studies show how NR4A1 in cancerous and non-cancerous tumour models in mice is consistently overexpressed, promoting tumour growth and progression.

However, mice studies also show that NR4A1 ligands, components that bind to the receptor, can reduce the pro-cancer effects of the receptor.

The receptor is now known to be an important nutrient sensor, where key dietary components such as flavonoids and other polyphenols, both of which are present in coffee, bind to the protein to activate subsequent health-protective molecular mechanisms.

The researchers, therefore, wanted to understand how certain health-boosting elements in brewed coffee may exhibit health-protective effects by binding to the NR4A1 receptor.

Polyphenols bind to NR4A1 receptors in cancer cells

The researchers used a range of analytical techniques, including fluorescence spectroscopy experiments and cellular assays, with soft tissue sarcoma cell lines to determine the interactions between N4RA1 and the major components of coffee.

The coffee components analysed included:

• Caffeic acid (polyphenol)
• Ferulic acid (polyphenol)
• Chlorogenic acid (polyphenol)
• Cinnamic acid derivatives
• Kahweol
• Cafestol
• Quinic acid

They found that although both caffeine and quinic acid were able to bind to the receptor, they had very weak functional effects. The researchers suggest further experiments to fully determine how NR4A1 regulates the effects of these components.

Importantly, they saw how major polyphenols, kahweol and cafestol were able to bind and act as inverse NR4A1 agonists.

These results suggest that major polyphenolic components in brewed coffee exhibit their health-protective function, at least in part, by binding to the NR4A1 receptor.

“What we’re saying is that at least part of coffee’s health benefits may come through binding and activating this receptor. Caffeine binds the receptor, but it doesn’t do much in our models. The polyhydroxy and polyphenolic compounds are much more active.” – Dr. Stephen Safe, professor in the Department of Veterinary Physiology and Pharmacology at Texas A&M University.

The NR4A1 receptor could play a central role in the health benefits of coffee

Polyphenols and flavonoids have long since been classified as anti-inflammatory and beneficial for health. However, based on previous research, the exact mechanism of action of these antioxidative components is unclear.

The research discussed here investigated how the key receptor NR4A1, a key transcription factor involved in ageing, wound repair, healing, and stress responses, is involved in mediating the function of polyphenols.

“There are many receptors and many mechanisms involved. What we’re showing is that this could be one of the important pathways. There’s still a lot of work to be done. We’ve made the connection, but we need to better understand how important that connection is.”  – Dr. Stephen Safe.

The study confirms that polyphenols bind to the receptor to induce NR4A1-dependent activities. But more research is still required to understand the exact mechanism of other components in coffee, such as caffeine and quinic acid.

Furthermore, polyphenols and other major coffee elements linked to health benefits are likely to work through other molecular pathways. More research is needed to understand these pathways and learn how exactly our daily cup of coffee can benefit health and wellbeing.

To read more research on molecular biology and nutrition, visit  the Open Access journal Nutrients or International Journal of Molecular Sciences. Alternatively, explore the full journal list.