Epigenetic changes promote development of fatty liver in mice and humans

January 10, 2017
The direct methylation of the DNA permanently changes the gene expression when it occurs in control regions of genes (so-called CpG islets) made accessible by the modification of the histones. Credit: © DIfE

Mice with a strong tendency to obesity already exhibit epigenetic changes at six weeks of age, inducing the liver to amplify its production of the enzyme DPP4 and release it into the circulation. Over the long term, this favors the development of a fatty liver. Such changes in DNA methylation are also detectable in humans with fatty liver and suggest a similar causal chain. These are the results of a study of an international research team led by Annette Schürmann, Robert Schwenk, Christian Baumeier and Sophie Saussenthaler of the German Institute of Human Nutrition (DIfE), a partner of the German Center for Diabetes Research (DZD).

The team, which includes diabetes researchers from Finland, Sweden and France, has now published its results in the journal Diabetes..

DPP4 is an enzyme that inhibits the action of important intestinal hormones of the glucose metabolism. Various studies have shown that high stimulate the body's production of the enzyme. In particular, people with non-alcoholic have high DPP4 levels in the liver and in the blood. Until now, however, it was unclear whether increased DPP4 is a consequence or a trigger of fatty .

To find answers to these questions, the scientists studied the gene regulation of the DPP4 gene in mice that are prone to obesity. Similar to identical twins, all animals of this breeding line are genetically identical. Nevertheless, some of the mice gain much more weight under the same high-fat diet and at the adult age of about 20 weeks, develop a fatty liver. This suggests that the differences in weight development are due to epigenetic effects.

In their study, the researchers showed that at the age of just six weeks, in the mice with rapid weight gain, the DPP4 gene was less methylated at four specific loci, i.e. epigenetically altered, compared to the other mice. As a result, the enzyme synthesis in the liver as well as the enzyme concentrations in the blood increased significantly, depending on the blood glucose level, even before the animals developed a fatty liver. "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. If the sites in the gene are methylated, the DPP4 synthesis in the is 'dimmed.' That means reduced and reversed," said Christian Baumeier, the first author of the publication.

Furthermore, the scientists observed that later, only those adult animals had a fatty liver that exhibited higher DPP4 levels due to reduced methylation. "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. Rather the opposite was true, the altered epigenetic regulation of the gene was responsible for the development of the fatty liver," added Sophie Saussenthaler, who shared the first authorship with Baumeier.

As further analyses have shown, the DPP4 gene in the human liver is regulated by just as in mice. In tissue samples from patients with severe fatty liver disease, the gene was less methylated. The degree of fat content in the liver correlated with the degree of DPP4 gene methylation and the amount of enzymes produced by the liver.

"Taken together, our results indicate that the epigenetic changes of the DPP4 gene associated with obesity have a negative effect on the already in young people, long before a fatty liver develops," said Annette Schürmann, leader of the study and head of the Department of Experimental Diabetology at DIfE. She continued: "Therefore, in further studies, we should investigate how and at what point DPP4 inhibitors can be used in diabetes therapy to prevent the development of non-alcoholic fatty liver disease."

Explore further: Epigenetic modification increases susceptibility to obesity and predicts fatty liver

More information: Christian Baumeier et al, HepaticDNA Methylation Associates With Fatty Liver, Diabetes (2017). DOI: 10.2337/db15-1716

Related Stories

Epigenetic modification increases susceptibility to obesity and predicts fatty liver

May 24, 2016
Scientists of the German Center for Diabetes Research (DZD), led by the German Institute of Human Nutrition (DIfE), have demonstrated that the epigenetic modification of the Igfbp2 gene observed in young mice precedes fatty ...

Fatty liver disease contributes to cardiovascular disease and vice versa

November 10, 2016
For the first time, researchers have shown that a bi-directional relationship exists between fatty liver disease and cardiovascular disease. Fatty liver disease can lead to increased cardiovascular disease risk and vice versa.

Long-term DPP4-inhibitor use not tied to fracture risk in T2DM

December 19, 2016
(HealthDay)—For patients with type 2 diabetes mellitus (T2DM), long-term use of dipeptidyl peptidase-4 inhibitors (DPP4-Is) is not associated with fracture risk, according to a study published online Dec. 10 in Diabetes, ...

Research links fatty liver disease to type 2 diabetes

October 18, 2016
Insulin resistance in the liver is a major factor in the development of type 2 diabetes, and it is almost always associated with too much fat in the liver—a condition called non-alcoholic fatty liver disease (NAFLD). The ...

Gene variant may increase risk of liver disease in obese youth

November 16, 2015
Researchers have found that a genetic variant is linked with an increased risk of fatty liver disease in obese youth; however, children with the variant tend to have lower total and LDL cholesterol levels.

Weight loss surgery alters fatty liver disease genes

August 6, 2013
Research has shown that weight loss surgery can benefit obese individuals in ways that go beyond shedding pounds, for example by causing early remission of type 2 diabetes. Now scientists have found that the surgery can also ...

Recommended for you

Scientists discover a new way to treat type 2 diabetes

July 21, 2017
Medication currently being used to treat obesity is also proving to have significant health benefits for patients with type 2 diabetes. A new study published today in Molecular Metabolism explains how this therapeutic benefit ...

Alzheimer's drug cuts hallmark inflammation related to metabolic syndrome by 25 percent

July 20, 2017
An existing Alzheimer's medication slashes inflammation and insulin resistance in patients with metabolic syndrome, a potential therapeutic intervention for a highly dangerous condition affecting 30 percent of adults in the ...

Diabetes or its precursor affects 100 million Americans

July 19, 2017
Almost one-third of the US population—100 million people—either has diabetes or its precursor condition, known as pre-diabetes, said a government report Tuesday.

One virus may protect against type 1 diabetes, others may increase risk

July 11, 2017
Doctors can't predict who will develop type 1 diabetes, a chronic autoimmune disease in which the immune system destroys the cells needed to control blood-sugar levels, requiring daily insulin injections and continual monitoring.

Diabetes complications are a risk factor for repeat hospitalizations, study shows

July 7, 2017
For patients with diabetes, one reason for hospitalization and unplanned hospital readmission is severe dysglycemia (uncontrolled hyperglycemia - high blood sugar, or hypoglycemia - low blood sugar), says new research published ...

Researchers identify promising target to protect bone in patients with diabetes

July 7, 2017
Utilizing metabolomics research techniques, NYU Dentistry researchers investigated the underlying biochemical activity and signaling within the bone marrow of hyperglycemic mice with hopes of reducing fracture risks of diabetics

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.