In 2022, Rosetrees Trust awarded a Seedcorn grant to Dr Thomas Marjot, supporting early-stage research into how metabolic processes contribute to liver disease. That early investment has now helped lead to an important new discovery: researchers at the University of Oxford have shown that the world’s most common liver disease follows a strong day–night rhythm, with the most harmful metabolic changes occurring overnight.

Published in Cell Metabolism, the study reveals that metabolic dysfunction-associated steatotic liver disease (MASLD) — formerly known as non-alcoholic fatty liver disease — is driven by metabolic changes that worsen at night, when the body is least able to process sugar and fat. Crucially, these night-time problems persist even after weight loss and reductions in liver fat, suggesting they may be an early and fundamental driver of disease.

MASLD affects around 40% of adults worldwide and is closely linked to obesity and insulin resistance. While often asymptomatic, severe forms can progress to cirrhosis, liver failure, liver cancer and cardiovascular disease, making it a major and growing global health challenge.

Mapping metabolism around the clock

To investigate whether MASLD follows a daily rhythm, researchers at Oxford carried out intensive metabolic studies during both the day and the night in people with and without the disease. These included liver biopsies and infusion-based tests of insulin sensitivity — an ambitious approach rarely performed in human studies.

The results were striking. The team found that overnight:

• Liver fat production increased

• Insulin resistance worsened not only in the liver, but also in muscle and abdominal fat tissue

• Blood insulin levels fell, further promoting fat accumulation in the liver

Together, these changes create a metabolic environment that strongly favours liver fat build-up during the night.

A harmful ‘double hit’

The researchers also identified a behavioural factor that may amplify this risk. Many participants with MASLD consumed a large proportion of their daily calories in the evening, with most eating over 40% of their daily energy intake at dinner.

This means the largest energy load often arrives at precisely the time when metabolism is most impaired — creating a damaging “double hit” that could accelerate disease progression.

Metabolic dysfunction persists after weight loss

Importantly, the study went on to explore whether unhealthy night-time metabolism was a cause or a consequence of MASLD. Even after participants lost weight and reduced fat in their liver, night-time metabolic dysfunction remained.

This suggests that altered metabolism at night may occur early in the disease process and could be a primary driver of MASLD, rather than simply a result of excess weight.

New opportunities for prevention and treatment

Lead author Dr Thomas Marjot, NIHR Academic Clinical Lecturer in Hepatology at the University of Oxford, explains:

“All the key pathways known to cause fat build-up in the liver worsened at night. This work offers opportunities to use the body’s natural rhythms to help treat MASLD — including optimising the timing of exercise and medications.”

The findings also deliver a clear message for patients: large evening meals are particularly harmful, as calories consumed late in the day are more likely to be stored in the liver.

Supporting early-stage innovation

This study illustrates the value of Seedcorn funding in enabling high-risk, high-reward research. By supporting Dr Marjot’s work in 2022, Rosetrees Trust helped catalyse a programme of research that has now generated insights with the potential to reshape how MASLD is prevented and treated.

Alongside support from the NIHR and Wellcome Trust, this work demonstrates how early investment in experimental medicine can deliver lasting impact for patients.