The most prevalent chronic liver condition worldwide is non-alcoholic fatty liver disease (NAFLD), a build-up of fat in the liver that isn’t caused by heavy alcohol use. Linked to genetics and overweight or obesity, if NAFLD is left untreated, it can progress into its most severe form, called NASH (non-alcoholic steatohepatitis), which is characterized by liver inflammation and scarring. NASH also increases the risk of liver failure and liver cancer.
Intermittent fasting has recently gained favor as a means of improving health, including liver health. In a new study, researchers from the German Cancer Research Center (DKFZ) and the University of Tübingen examined the effects of an intermittent fasting regime on liver disease.
“The vicious cycle 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,” said Mathias Heikenwälder, from DKFZ and the University of Tübingen and co-corresponding author of the study. “We have therefore investigated whether simple dietary changes can specifically interrupt this fatal process.”
The researchers fed mice a Western-type diet high in fats and sugars for 32 weeks to induce NASH. One group of mice remained on an all-you-can-eat Western diet, while another was placed on a 5:2 intermittent fasting regime: two non-consecutive days without food (but free access to water) each week.
As expected, the mice with access to unlimited food gained weight and body fat and developed chronic liver inflammation. In contrast, despite eating more on non-fasting days, the intermittent fasting group didn’t gain weight, showed fewer signs of liver disease and had lower levels of biomarkers indicating liver damage. The researchers concluded that the 5:2 diet caused the mice to be resistant to the development of NASH. Experimenting with the length and frequency of fasting periods, the researchers found that a 5:2 regime worked better than a 6:1 regime and that fasting for 24 hours was better than fasting for 12.
Comparing the protein composition, metabolic pathways, and gene activity in the livers of fasting and non-fasting mice identified two proteins responsible for the protective fasting response: PPAR-alpha and PCK1. PPAR-alpha is a major regulator of fat metabolism in the liver and necessary for ketogenesis, the breakdown of fatty acids to produce ketone bodies and a response to prolonged fasting. PCK1 is an enzyme responsible for regulating the biosynthesis of glucose from certain non-carbohydrate carbon sources (gluconeogenesis).
“The fasting cycles lead to profound metabolic changes, which together act as beneficial detoxification mechanisms and help to combat MASH*,” Heikenwälder said.
When PPAR-alpha and PCK1 were genetically knocked out in the liver cells of mice, intermittent fasting didn’t prevent either chronic inflammation or liver scarring. The proteins appear in reduced levels in tissue samples from humans with NASH, too.
An existing drug, pemafibrate (sold as Parmodia), mimics the effects of PPAR-alpha to lower triglycerides, a type of fat that circulates in the blood and can, when high, contribute to artery hardening or thickening. When given to mice, pemafibrate produced some of the metabolic changes seen in the 5:2 diet mice but only partially produced the protective effects that fasting produced.
“This is hardly surprising, as we can only influence one of the two key players with pemafibrate,” said Heikenwälder. “Unfortunately, a drug that mimics the effects of PCK1 is not yet available.”
The 5:2 intermittent fasting diet also reduced existing, chronic liver inflammation caused by NASH. After a further four months intermittently fasting, mice with NASH caused by eating a Western diet had better blood values, less fatty livers and liver inflammation and they developed less liver cancer.
“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,” Heikenwälder said. “The promising results justify studies in patients to find out whether intermittent fasting protects against chronic liver inflammation as well as [it does] in the mouse model.”
* MASH (metabolic dysfunction-associated steatohepatitis) is another term for NASH. While the press release refers to MASH, the published paper refers to NASH.
The study was published in the journal Cell Metabolism.
Source: DKFZ