International Metabolic Health Day (10th Oct)

Dr Brendan Norman & Dr Juliette Hughes
Department of Musculoskeletal and Ageing Science, University of Liverpool.
October 2025.

A new global event to promote metabolic health

October 10th marks the first International Metabolic Health Day. This global event is designed to raise awareness and support for metabolic health and research into how metabolic balance affects overall wellness. “Metabolic health is the foundation upon which our vitality and resilience are built”, writes Dr Natasha Winters, organiser of the event and founder of the Metabolic Terrain Institute of Health.

The Metabolic Health Day Terrain Ten™ and AKU

The ‘terrain ten’ refers to ten key factors that influence metabolic health:

• Inflammation
• Insulin resistance
• Oxidative stress
• Hormonal imbalances
• Toxic burden
• Immune system dysfunction
• Poor mitochondrial health
• Microbiome imbalance
• Mental/emotional stress
• Nutritional deficiencies

We can think of inherited metabolic disorders, such as AKU, as presenting a unique set of metabolic challenges – a unique ‘terrain’ for patients to navigate. Research being led by our team here at the University of Liverpool addresses a number of these key factors in the context of AKU.

Toxic burden – spotlight on the kidney

Toxic build-up of the metabolite homogentisic acid (HGA) has long been established as the central cause of disease in AKU. The repurposing of nitisinone, led by researchers here in Liverpool, has been a major breakthrough in the treatment of AKU. Nitisinone is the most effective known agent for preventing the formation of HGA and subsequent ochronosis of tissues. Unfortunately, nitisinone is not a cure for AKU. Whilst nitisinone deals with the toxic burden of HGA, its use results in the build-up of other molecules from which HGA is produced. One of these molecules is tyrosine. High blood tyrosine levels, known as ‘tyrosinemia’ also has potential for harmful effects on the body. 

A major focus of our current research is to explore new ways to prevent tyrosinemia for patients taking nitisinone. Tyrosine is known as an amino acid. Amino acids serve many important functions in the body and are commonly referred to as the ‘building blocks’ of proteins, which make up the tissues of the body. A balance in the intake/production of amino acids versus their breakdown is key in metabolic health. 

The kidney is an important organ in regulating amino acids, as it normally serves to reclaim amino acids in a process referred to as ‘reabsorption’. Reabsorption prevents these useful molecules from being eliminated in the urine so they can participate in other useful metabolic processes. In our laboratory, we have recently shown that it is possible to selectively alter the reabsorption process for tyrosine with minimal effects on other related amino acids. Using a molecule specifically designed to inhibit the activity of a key kidney protein that acts as a transporter for tyrosine in the reabsorption process, we have demonstrated a significant reduction in blood tyrosine in a mouse model of nitisinone-induced tyrosinemia. These encouraging data indicate clear potential for this approach to be explored in patients with AKU in coming years.

Another approach to address toxic HGA burden being explored within our group is restoration of HGD, the defective enzyme in AKU. Rebecca Brown is a PhD student in our laboratory investigating delivery of mRNA encoding the HGD enzyme in our mouse model of AKU. 

Rebecca Brown, a PhD student in our laboratory researching mRNA therapy as a potential approach to prevent toxic HGA build up in AKU.

Oxidative stress in AKU

Our cells are constantly exposed to stressors in various forms. A major group of stressors is those that induce oxidative damage to cells and their constituents, including UV radiation from sunlight, environmental pollutants, and even molecules produced from normal chemical processes occurring within the body. If not adequately controlled, these stressors can induce a pathological state of ‘oxidative stress’. Our laboratory is currently investigating the idea that the HGA molecule in AKU induces a unique form of oxidative stress. Back in 2017, our laboratory showed for the first time the presence of a reactive ‘free radical’ form of HGA in heavily pigmented cartilage donated by a patient with AKU.1  

We are exploring the idea that oxidative stress associated with HGA and related molecules may underly damage to tissues including cartilage and the brain in AKU. Funding for two PhD studentships from the AKU society is helping us address the following questions:

• What effect does long-term exposure to HGA/tyrosine have on the function of cartilage and brain cells?
• What are the chemical properties of HGA and related molecules that lead them to contribute to oxidative stress?
• Can any known agents prevent/reverse these pathological changes?

Is AKU a risk factor for neurodegenerative disorders?2

Microbiome imbalance

The gut microbiome is becoming increasingly recognised as a major mediator of metabolic health. Several years ago, it was shown that HGA has antibacterial properties.3 We are currently investigating whether exposure to HGA affects the bacterial composition of the gut in our AKU mouse model. To do this, we are using state of the art gene sequencing technology to assess the bacterial composition of fecal samples.

Assessing metabolism in our laboratory: models and molecules

We use various model systems to assess the effects of molecules such as HGA and candidate treatment agents. These models range from cultures of cells maintained in a dish to mice with HGD gene mutations. We also study patient samples, such as blood and urine samples collected in the various clinical studies of nitisinone in AKU. The samples we obtain from these studies are very complex in their composition – often containing thousands of different biochemicals. We are particularly interested in a class of small biological molecules known as metabolites – HGA and tyrosine are examples, as are glucose and cholesterol amongst many other small molecules. The overall metabolite composition, known as the ‘metabolome’, of these different samples is a very sensitive indicator of metabolic health. Metabolome profiles therefore provide us with essential information in our research into AKU, enabling us to address questions such as the effect nitisinone has on the processes that influence overall metabolic health. 

How do we detect so many chemicals at once in a single sample? Separation and measurement of metabolites in complex biological samples is a significant challenge – and a whole field of scientific research in its own right. We use a technique called mass spectrometry, which in simple terms can be thought of as an extremely precise weighing scale for small molecules present in the body, such as HGA and tyrosine. This enables us to separate and measure specific molecules of interest in our research according to the ‘weight’ of their unique chemical structures. When we combine the information from different metabolites within a sample together, we have a ‘snapshot’ of metabolic health status for a patient or the model system we are studying. This snapshot is a key readout in our research into different aspects of metabolic health in AKU.

1 Chow et al. Pigmentation Chemistry and Radical-Based Collagen Degradation in Alkaptonuria and Osteoarthritic Cartilage. Angew Chem Int Ed Engl. 2020;59(29):11937-11942. doi: 10.1002/anie.202000618. 

2 Ranganath L et al. Increased prevalence of Parkinson’s disease in alkaptonuria. JIMD Rep. 2023;64(4):282-292. doi: 10.1002/jmd2.12367. 

3 Ooi et al. Evaluation of Homogentisic Acid, a Prospective Antibacterial Agent Highlighted by the Suitability of Nitisinone in Alkaptonuria 2 (SONIA 2) Clinical Trial. Cells. 2023;12(13):1683. doi: 10.3390/cells12131683.