An international research team found detectable DNA methylation changes in obesity-prone mice that were only six-weeks old, that eventually promote the development of non-alcoholic fatty liver disease. The same changes can be found in humans with fatty liver, and suggest a target for treatment.
In question was the enzyme DPP4, which is found in high levels in the liver and the blood of people with non-alcoholic fatty liver disease (NAFLD). Prior to this research, scientists did not know whether high levels of DPP4 was a trigger of fatty liver disease or a result.
Without treatment, NAFLD can turn into cirrhosis of the liver, which can be life-threatening. NAFLD is the most common chronic liver disease in the U.S., and often occurs in hand with obesity and type 2 diabetes.
Researchers, led by Annette Schürmann, Robert Schwenk, Christian Baumeier and Sophie Saussenthaler of the German Institute of Human Nutrition, investigated gene regulation of DPP4 in mice with a strong tendency to obesity.
Even though the mice were genetically identical, some gained significantly more weight when fed the same high-fat diet and went on to develop fatty liver disease around 20 weeks old. The researchers suspected the differences were due to epigenetic changes.
The findings show that in mice who experienced rapid weight gain, the DPP4 was already epigenetically altered at the age of six weeks (there was reduced methylation of the DPP4 genes at four specific loci). Due to this, enzyme concentrations were already significantly elevated in the blood even prior to the mice developing fatty liver disease.
“Perhaps the methylation of the gene can be compared with a dimming switch, which regulates the transcription of the gene and thus the amount of the enzyme formed,” said Baumeier, first author in a statement. “If the sites in the gene are methylated, the DPP4 synthesis in the liver cells is ‘dimmed’, that means reduced and reversed.”
“Our results clearly show that the increased concentrations of DPP4 in the liver and blood that were measured in the obese animals were not the consequence of a fatty liver,” said Saussenthaler, also first author on the paper, in a statement. “Rather the opposite was true, the altered epigenetic regulation of the gene was responsible for the development of fatty liver.”
The scientists also evaluated tissue samples of patients with fatty liver disease and found that just as in mice, the gene was less methylated. The amount of DPP4 gene methylation and the number of enzymes made by the liver corresponded to the degree of fat content in the liver.
Schürmann said that results suggest that negative effects on the liver metabolism are already occurring in young people because of epigenetic changes of the DPP4 gene associated with obesity, even before fatty liver disease develops.
More studies are needed to see if DPP4 inhibitors can be utilized in diabetes treatment to stop non-alcoholic fatty liver disease from developing, Schürmann added.
DPP4 inhibitors are already used as a diabetes therapy to increase insulin secretion after people with type 2 diabetes eat food.
The findings of the study were published in the journal Diabetes.