Fructokinase—also known as ketohexokinase (KHK)—is the enzyme that kickstarts the metabolism of fructose. The term enzyme describes a macromolecule that catalyzes (speeds up) biological processes in our body (Parks et al., 1957). Fructokinase C (one type of fructokinase) has high affinity (highly reactive) to fructose molecules in the liver, small intestine, and kidney cortex initiating the process of fructose metabolism. Unlike glucose, which is metabolized through tightly regulated pathways, fructose is rapidly processed by fructokinase, converting it into fructose-1-phosphate using ATP (energy molecules). This lowered concentration of energy in the cell results in production of uric acid, contributing to impaired mitochondrial function – the core machinery of cellular energy production (Andres-Hernando et al., 2020).  

Fructose must react with fructokinase to begin its metabolism and generate end products such as uric acid; without fructokinase, fructose cannot be metabolized by the cell. Therefore, the mechanism of mediating the effect fructose has on our metabolic health relies on understanding and controlling the activity of fructokinase that is the key determinant of fructose metabolism. Excessive activation by the enzyme can disrupt cellular energy, drive fat gain, and impair hormonal signals like leptin and insulin.

Liv3 Health is aiming to explore and address the importance of the relationship between fructose and its catalyzing enzyme fructokinase in order to promote healthier dietary choices through SugarShield.

Fructokinase doesn’t just metabolize fructose—it accelerates it. As any other enzyme its primary role is to speed up reactions, not to create them. Fructokinase activity is unregulated – it rapidly acts in presence of fructose, leading to ATP consumption and producing byproducts like uric acid. By trapping fructose inside the cell and converting it into fructose-1-phosphate, fructokinase initiates a cascade of metabolic stress that can contribute to fat accumulation, mitochondrial dysfunction, and inflammation – especially when fructose intake is excessive (Andres-Hernando et al., 2017).

In fact, one of the reasons fructose is so uniquely damaging isn’t just that it’s a sugar – it’s how quickly and completely fructokinase allows it to take over. Fructokinase stays active until there are no fructose molecules left to metabolise due to lack of significant feedback inhibition. This unchecked activity can lead to rapid ATP depletion, triggering downstream effects such as:

- Induced oxidative stress - a change of the cell prooxidants and oxidants balance that leads to disrupted cell signalling and metabolic dysfunction (Sies, 1985).

- Generate uric acid, contributing to gout and cardiovascular problems (Muriel et al., 2021). 

- Drive de novo lipogenesis - the conversion of sugar into fat in the liver (Jung et al., 2022).

- Impair insulin signaling by overwhelming energy balance mechanisms (Wu et al., 2022). 

As fructokinase is active even in low presence of fructose, we can experience fructose metabolism even in modest intake. However, the effects are still dose dependent – as most other enzymes fructokinase activity rate is highly dependent on substrate (fructose) amount. Therefore, concerns are mainly with added fructose (like high fructose corn syrup) in processed foods and beverages that lead to overconsumption.

Importantly, fructokinase doesn’t just respond to dietary sugar. Endogenous fructose production - when your body generates fructose internally through the polyol pathway with help of sorbitol (carbohydrate derived from sugars also known as polyol) – triggered by high glucose, salt, or dehydration as well triggers fructokinase activity. That means its effects can be felt even on a low-sugar or sugar-free diet. Unlike glucose, fructose is metabolised up to ten times faster because of fructokinase. This means endogenous fructose generated inside cells is almost immediately metabolized by fructokinase, contributing to cellular energy disruption.

Studies have highlighted the importance of regulating fructokinase activity, particularly in conditions like ischemic acute kidney injury (iAKI) and diabetic nephropathy, where endogenous fructose production is elevated. Research shows that inhibiting fructokinase in these settings can reduce the risk of metabolic dysfunction and prevent cellular energy (Andres-Hernando et al., 2017; Lanaspa et al.p, 2014)

SugarShield aims to block fructose’s harmful pathway, allowing your body to maintain healthier energy production and improve overall metabolic health. The mechanism underlying SugarShield fructose control is liposomal delivery of active ingredients: luteolin - a flavonoid found in various fruits and vegetables that enhances anti-inflammatory and antioxidant defenses and has been shown to directly inhibit fructokinase; tart cherry extract, rich in anthocyanins, also supports metabolic health by lowering inflammation and uric acid. By blocking fructokinase we aim to stop fructose from draining cellular energy and restore your energy and improve metabolic health.

These statements have not been evaluated by the FDA. This product is not intended to diagnose, treat, cure, or prevent any disease.

In rare cases, mutations in both copies of KHK  (which encodes fructokinase) gene result in fructokinase deficiency - a recessive genetic condition called essential fructosuria. Without functional fructokinase, our body is not capable of initiating the process of fructose metabolism (Hannou et al., 2018). Since fructose is not metabolized or stored, it builds up in the blood and is filtered out by the kidneys and then eliminated through urine. While this condition is benign, it provides an important clue of possible pharmacological inhibition of fructokinase: when fructokinase is absent, fructose is excreted with urine rather than metabolized into harmful byproducts. This has inspired interest in potential fructokinase inhibitors including natural compounds like luteolin, which have shown promise in animal studies for reducing liver fat, uric acid, and insulin resistance (Yao et al., 2023).

These statements have not been evaluated by the FDA. This product is not intended to diagnose, treat, cure, or prevent any disease.

Given its role as the metabolic start point for fructose metabolism, fructokinase has become a focal point in research on metabolic syndrome, non-alcoholic fatty liver disease, cell energy depletion and even neurodegeneration. The benign nature of essential fructosuria further supports the feasibility and safety of fructokinase inhibition. By targeting this single enzyme, it may be possible to prevent or reverse multiple downstream effects of fructose metabolism – especially in a world where endogenous fructose is increasingly common. Research is now focusing on natural compounds like luteolin and tart cherry extract, aiming to inhibit fructokinase activity and reduce inflammation and production of byproducts. These ingredients are being studied for their potential in supplements aimed at supporting healthy metabolism, energy balance, and weight control.

• Ana Andres-Hernando, Nanxing Li, Christina Cicerchi, Shinichiro Inaba, Wei Chen, Carlos Roncal-Jimenez, Myphuong T. Le, Michael F. Wempe, Tamara Milagres, Takuji Ishimoto, Mehdi Fini, Takahiko Nakagawa, Richard J. Johnson & Miguel A. Lanaspa. (2017). Protective role of fructokinase blockade in the pathogenesis of acute kidney injury in mice. Nature communications, 8(14181). https://doi.org/10.1038/ncomms14181
• Andres-Hernando, A., Orlicky, D. J., Kuwabara, M., Ishimoto, T., Nakagawa, T., Johnson, R. J., & Lanaspa, M. A. (2020). Deletion of Fructokinase in the Liver or in the Intestine Reveals Differential Effects on Sugar-Induced Metabolic Dysfunction. Cell metabolism, 31(1), 117-127. https://doi.org/10.1016/j.cmet.2020.05.0
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