Non-alcoholic fatty liver disease is the most common chronic liver disease and can have serious consequences, since if not treated properly it can cause liver inflammation (steatohepatitis associated with metabolic dysfunction), cirrhosis, and even liver cancer. This disease is closely related to obesity, a global public health problem that is associated with an increase in cases of liver failure and liver cancer.
Mathias Heikenwälder from the German Cancer Research Center (DKFZ) and the University of Tübingen explains that the destructive cycle of an unhealthy diet, obesity, liver inflammation and liver cancer causes great suffering and represents a considerable burden for health systems. Therefore, his team investigated whether making simple changes to the diet could interrupt this deadly process.
Previous studies have already shown that intermittent fasting is effective in reducing weight and relieving certain metabolic disorders, and Heikenwälder’s team has tested in mice whether this approach can also protect the liver from fatty degeneration and chronic inflammation.
The animals were fed a diet high in sugars and fats, similar to the typical Western diet. One group of mice had constant access to food. As expected, these animals gained weight and body fat and developed chronic liver inflammation. On the other hand, the mice in the other group did not eat two days a week (5:2 intermittent fasting), but they could 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. Interestingly, resistance to the development of a fatty liver was independent of total caloric intake, as animals compensated for lost rations at the end of fasting periods.
The most effective dietary pattern against liver inflammation
Experimenting with different variants of intermittent fasting, it was found that several factors determine protection against liver inflammation: the number and duration of fasting cycles, as well as the start of the fasting phase. A 5:2 dietary pattern works better than a 6:1 one; 24-hour fasting phases are better than 12-hour fasting phases. An especially unhealthy diet requires more frequent diet cycles.
Heikenwälder’s team also explored the molecular background of the fasting response. They compared protein composition, metabolic pathways and gene activity in the liver of fasting and non-fasting mice. They highlighted two main players responsible for the protective fasting response: the transcription factor PPARα and the enzyme PCK1, which work together to increase fatty acid breakdown and gluconeogenesis, and inhibit fat accumulation.
Studies on tissue samples from patients with steatohepatitis associated with metabolic dysfunction also showed the same molecular pattern with reductions in PPARα and PCK1. Furthermore, when both proteins were genetically inactivated simultaneously in the liver cells of the mice, intermittent fasting could not prevent either chronic inflammation or fibrosis.
On the other hand, the drug pemafibrate mimics the effects of PPARα in the cell. This drug is a selective PPARα modulator approved in Japan, which has demonstrated in pivotal studies a positive action on lipid profiles and insulin resistance in patients with type 2 diabetes and hypertriglyceridemia.
“5:2 intermittent fasting has great potential to prevent steatohepatitis associated with metabolic dysfunction and liver cancer and in the treatment of chronic liver inflammation”
The researchers found that although it induced some of the favorable metabolic changes seen with 5:2 fasting, it could only partially mimic the protective effects of fasting. “This is not surprising, since with pemafibrate we can only influence one of the two key players. Unfortunately, a drug that mimics the effects of PCK1 is not yet available,” explains Mathias Heikenwälder.
Finally, Heikenwälder and his team investigated whether the 5:2 diet could also alleviate existing chronic liver inflammation. After four additional months of 5:2 intermittent fasting, the mice showed better blood values, less fatty liver and inflammation and, above all, they developed less liver cancer and had fewer carcinogenic foci in the liver.
“This shows that 5:2 intermittent fasting has great potential, both in the prevention of steatohepatitis associated with metabolic dysfunction and liver cancer, and in the treatment of chronic liver inflammation,” summarizes lead researcher Heikenwälder. “The promising results justify studies in patients to find out if intermittent fasting protects against chronic liver inflammation as has been observed in the mouse model.”
This fasting regimen is considered easy to integrate into everyday life, as fasting days can be tailored to personal needs and specific foods are not prohibited. Heikenwälder emphasizes that although there will always be people who cannot maintain a strict diet long-term, they will continue to investigate drug combinations that can fully mimic the protective effects of fasting.
