Research conducted by scientists at the German Cancer Research Centre (DKFZ) and the University of Tubingen has demonstrated that intermittent fasting on a 5:2 schedule can mitigate the progression of fatty liver disease and reduce the risk of liver cancer in mice. Fatty liver disease, particularly nonalcoholic fatty liver disease (NAFLD), is a prevalent chronic liver disorder often associated with obesity and can lead to serious complications such as liver inflammation (metabolic dysfunction-associated steatohepatitis, MASH), cirrhosis, and even malignancy.
In the study, mice were fed a high-sugar and high-fat diet resembling a typical Western diet. One group of mice had continuous access to food and exhibited weight gain, increased body fat, and chronic liver inflammation. Conversely, another group of mice practiced intermittent fasting on a 5:2 schedule, where they fasted on two non-consecutive days per week but could eat ad libitum on the other days. Despite being on the same high-calorie diet, these fasting mice did not gain weight, showed fewer signs of liver disease, and had lower levels of biomarkers indicating liver damage. They displayed resistance to the development of MASH, even though they immediately compensated for the lost calories after fasting periods.
Further investigation revealed that the protective effects of intermittent fasting against liver inflammation depended on various factors, including the number and duration of fasting cycles and the timing of fasting phases. A 5:2 dietary pattern and 24-hour fasting phases were found to be more effective than other variants.
“The vicious circle of an unhealthy diet, obesity, liver inflammation and liver cancer is associated with major restrictions and suffering for those affected and also represents a considerable burden on healthcare systems,” states Mathias Heikenwalder, DKFZ and University of Tubingen. “We have therefore investigated whether simple dietary changes can specifically interrupt this fatal process.”
Molecular analysis identified two key players responsible for the protective effects of fasting: the transcription factor PPARa and the enzyme PCK1. These molecules work together to increase the breakdown of fatty acids and gluconeogenesis while inhibiting fat accumulation in the liver.
The relevance of these findings to humans was confirmed by examining tissue samples from MASH patients, which showed a similar molecular pattern with reduced levels of PPARa and PCK1.
“The fasting cycles lead to profound metabolic changes, which together act as beneficial detoxification mechanisms and help to combat MASH,” states Heikenwalder, summarizing the molecular details.
Further experiments demonstrated that genetically switching off both PPARa and PCK1 in the liver cells of mice eliminated the protective effects of intermittent fasting. Additionally, a drug called pemafibrate, which mimics the effects of PPARa, partially replicated the benefits of fasting but was not as effective.
“This is hardly surprising, as we can only influence one of the two key players with pemafibrate. Unfortunately, a drug that mimics the effects of PCK1 is not yet available,” explains Mathias Heikenwalder.
Moreover, the researchers investigated whether intermittent fasting could alleviate existing chronic liver inflammation. Mice with established MASH who underwent four months of 5:2 intermittent fasting exhibited better blood values, reduced fatty liver and liver inflammation, and fewer instances of liver cancer compared to non-fasting mice.
“This shows us that 5:2 intermittent fasting has great potential – both in the prevention of MASH and liver cancer, as well as in the treatment of established chronic liver inflammation,” summarizes principal investigator Heikenwalder. “The promising results justify studies in patients to find out whether intermittent fasting protects against chronic liver inflammation as well as in the mouse model.”
Overall, the study suggests that intermittent fasting, particularly on a 5:2 schedule, may offer protective effects against fatty liver disease and liver cancer by modulating specific molecular pathways involved in metabolism and inflammation.
The 5:2 fasting regimen is popular. It is considered comparatively easy to integrate into everyday life, as the fasting days can be tailored to personal needs and no specific foods are prohibited. “Nevertheless, there will always be people who can’t stick to a strict diet in the long term,” states Heikenwalder. “That’s why we want to continue to investigate which combinations of drugs we can use to fully mimic the protective effects of fasting.”
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