Did you know that intermittent fasting protects against liver inflammation and liver cancer?

Heidelberg: Fatty liver disease often causes chronic liver inflammation and can potentially lead to liver cancer. Scientists from the German Cancer Research Center (DKFZ) and the University of Tübingen have shown in mice that intermittent fasting on a 5:2 schedule can block this progression.

Fasting reduces the development of liver cancer in mice that already have liver inflammation. The researchers discovered two proteins in liver cells that are both responsible for the beneficial effects of fasting. An approved drug can partially replicate this effect.

Non-alcoholic fatty liver disease is the most common chronic liver disease. It can have catastrophic consequences:
If left unchecked, it can cause liver inflammation (metabolic dysfunction-associated steatohepatitis, MASH), cirrhosis and even malignancy. It is often thought that fatty liver disease is a direct result of obesity. Obesity is increasingly common in emerging countries such as India and China, in addition to Europe and the United States. As a result, the number of cases of liver failure and cancer is rapidly increasing in the affected countries.

“The vicious circle of unhealthy diet, obesity, liver inflammation and liver cancer is associated with great disability and suffering for those affected and also represents a significant burden for healthcare systems,” says Mathias Heikenwalder, DKFZ and University of Tübingen. “We therefore investigated whether simple dietary changes could specifically interrupt this fatal process.”

Intermittent fasting has been shown in several studies to be an effective means of reducing weight and alleviating certain metabolic disorders. Heikenwalder’s team has now tested in mice whether this approach can also protect the liver against fatty degeneration and chronic inflammation.

The animals were fed a diet high in sugar and fat that corresponded to the typical Western diet. One group of mice had constant access to the food. As expected, these animals gained weight and body fat and developed chronic liver inflammation.

The mice in the other group were given nothing to eat two days a week (5:2 intermittent fasting, or 5:2 IF for short), but were allowed to eat as much as they wanted on the other days. Despite the high-calorie diet, these animals did not gain weight, showed fewer signs of liver disease and had lower levels of biomarkers that indicate liver damage. In short, they were resistant to the development of MASH.

Interestingly, resistance to the development of fatty liver disease was independent of total caloric intake, as the animals immediately made up for the lost ration after the end of the fasting period.

When experimenting with different variants of intermittent fasting, it turned out that different parameters determine the protection against liver inflammation: the number and duration of fasting cycles play a role, as does the start of the fasting phase. A 5:2 diet works better than 6:1; 24 hour fasting phases are better than 12 hour phases. A particularly unhealthy diet requires more frequent diet cycles.

Heikenwalder’s team now wanted to determine the molecular background of the fasting response. To this end, the researchers compared the protein composition, metabolic pathways and gene activity in the liver of fasting and non-fasting mice. Two key players emerged as responsible for the protective fasting response: the transcription factor PPARα and the enzyme PCK1. The two molecular players work together to increase fatty acid breakdown and gluconeogenesis and inhibit fat buildup.

“The fasting cycles lead to profound metabolic changes, which together act as beneficial detoxification mechanisms and help combat MASH,” says Heikenwalder, summarizing the molecular details.

That these correlations are not just a mouse phenomenon was demonstrated when tissue samples from MASH patients were examined: here too, the researchers found the same molecular pattern with reduced PPAR a and PCK1. Are PPAR a and PCK1 actually responsible for the beneficial effects of fasting? When both proteins were simultaneously genetically disabled in the mice’s liver cells, intermittent fasting failed to prevent chronic inflammation or fibrosis.

The drug pemafibrate mimics the effects of PPARa in the cell. Can the substance also imitate the protective effect of fasting? The researchers investigated this question in mice.

Pemafibrate induced some of the beneficial metabolic changes observed with 5:2 fasting. However, it was only partially able to mimic the protective effects of fasting. “This is not surprising, since with pemafibrate we can only influence one of the two main players. Unfortunately, there is no drug available yet that mimics the effects of PCK1,” explains Mathias Heikenwalder.

While Heikenwalder and his team initially focused on the effects of intermittent fasting on the prevention of MASH, they next investigated whether the 5:2 diet could also alleviate existing chronic liver inflammation.

To do this, the team examined mice that had developed MASH after being fed a high-sugar, high-fat diet for months. After a further four months of 5:2 intermittent fasting (on the same diet), these animals were compared to the non-fasted control group. The fasting mice had better blood values, less fatty liver disease and liver inflammation and, above all, they developed less liver cancer and had fewer cancer foci in the liver.

“This shows us that 5:2 intermittent fasting has great potential – both in the prevention of MASH and liver cancer, and in the treatment of established chronic liver inflammation,” summarizes lead researcher Heikenwalder. “The promising results warrant studies in patients to find out whether intermittent fasting protects against chronic liver inflammation, as well as in the mouse model.”

The 5:2 fasting regimen is popular. It is considered relatively easy to integrate into everyday life because the fasting days can be tailored to personal needs and no specific foods are prohibited. “Yet there will always be people who cannot stick to a strict diet in the long term,” says Heikenwalder. “That is why we want to continue investigating which combinations of drugs we can use to fully mimic the protective effects of fasting.” (ANI)