The researchers also found that these night-time problems continue even after people lose weight and reduce fat in their liver. Their findings suggest that these night-related metabolic issues may be an important driver of the disease.
Metabolic dysfunction-associated steatotic liver disease (MASLD) – formerly known as non-alcoholic fatty liver disease – is the most common liver disease worldwide, affecting around 40% of adults. Severe forms can lead to cirrhosis, liver failure, liver cancer and cardiovascular disease. MASLD is closely associated with being overweight and is characterised by insulin resistance, a key driver of fat accumulation in the liver.
During the study, published in Cell Metabolism, the research team – who are supported by the National Institute for Health and Care Research (NIHR) Oxford Biomedical Research Centre and Oxford Health Biomedical Research Centre – used intensive metabolic investigations during the day and night in people with and without MASLD, including biopsies and infusion-based tests of insulin sensitivity.
This approach enabled them to map how key drivers of liver fat accumulation change over 24 hours. They showed that liver fat production increased overnight and that insulin resistance worsened not only in the liver, but also in muscle and abdominal fat tissue. Blood insulin levels also fell during the night, further amplifying the processes that promote fat build-up in the liver.
'Double hit'
In addition, the team observed that many people with MASLD tended to consume a large proportion of their daily calories in the evening. In the study, most participants ate more than 40% of their total daily energy intake at dinner, meaning the biggest energy load often arrived at the very time metabolism is most impaired. This combination may create a harmful 'double hit' that could accelerate MASLD.
The findings suggest that targeting metabolism during this vulnerable night-time window could offer new approaches to the prevention and treatment of MASLD.
Dr Thomas Marjot, NIHR Academic Clinical Lecturer in Hepatology at the University of Oxford and lead author of the study, is affiliated with RDM's Oxford Centre for Diabetes, Endocrinology and Metabolism. He said: 'Some diseases are already known to fluctuate across the day – for example, symptoms of asthma can worsen overnight, and rheumatoid arthritis is often worse in the morning. However, because MASLD is frequently asymptomatic or causes non-specific symptoms, it has always been unclear whether it follows a daily rhythm.
'To work this out, we had to perform very detailed metabolic investigations during both the day and the night. Our findings were really striking — all the key pathways known to cause fat build-up in the liver worsened at night: the body was far less responsive to insulin, the liver produced more fat, and muscle and abdominal fat tissue couldn't perform their metabolic functions effectively.'
Dr Marjot added: 'We then wanted to understand whether unhealthy night-time metabolism was a cause or an effect of MASLD — which came first? Importantly, we saw that metabolic dysfunction at night persisted even after patients lost weight and reduced the fat in their liver. This suggests that altered metabolism at night may occur early and could be a primary driver of MASLD.
'This work offers exciting opportunities to use the body's natural rhythms to help treat MASLD, including optimising the timing of exercise and helping to inform the best time of day to take medications. Our study also clearly shows that for patients with MASLD, having a large evening meal is a bad idea. Consuming lots of calories just before bed, when the body is less able to process food efficiently, means that sugar and fat are more likely to end up being stored in the liver.'
Patient perspective
One of the participants in the trial was 43-year-old Rowan Waller from Oxford. He discovered he had MASLD after routine blood tests showed elevated liver enzymes and an ultrasound scan confirmed a fatty liver.
Rowan said: 'I first met the study researchers in a hospital clinic after being told I had MASLD. At this point I was keen to try and lose some weight and improve my overall health. Although the study involved quite a lot of investigations, I had a vague fear of missing out if I didn't do it. I knew I was going to get some health benefit and I was interested to understand how my liver was working both day and night.'
Rowan then went on to have day and night investigations before and after a 12-week commercially available weight-loss programme.
'I managed to lose two stone (14 kg) and it was great to see my metabolism improve in real-time across the course of the study. Having been involved in research, I am now much more conscious of my lifestyle including eating and drinking habits. I often don't drink - even when going to watch football – and I am also trying to avoid fatty foods, particularly in the evening.'
NIHR Oxford Health BRC Director, Professor Rachel Upthegrove said: 'It is fantastic to see such ambitious experimental medicine studies performed in humans. This study gives a powerful insight into how altered diurnal rhythms can lead to liver damage, which has implications for how we understand and treat not only MASLD but other metabolic diseases including obesity, insulin resistance, and diabetes.'
As well as the NIHR, this research was supported by the Wellcome Trust and Rosetrees Trust.