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A view into the genome provides information on the lipid metabolism

Since its foundation around 10 years ago, the VIVIT institute in Dornbirn and Feldkirch has been dealing with the impact of disorders of the sugar and lipid metabolisms on the pathogenesis of diseases such as atherosclerosis, liver damage or coronary heart disease. In a genetic association study, researchers at the institute have recently been able to show that DNA variations in chromosome 1 are associated with cholesterol as well as with angiographically determined coronary heart disease. However, the researchers also assume that metabolic disorders such as haemochromatosis or celiac disease are the result of both genetic causes and environmental factors.

Fully differentiated fat cells are cultivated at the VIVIT institute in order to model the generation of fatty tissue and gain deeper insights into these processes. © VIVIT

The basic research carried out by the Vorarlberg Institute of Vascular Investigation and Treatment (VIVIT) focuses mainly on the analysis of fat cells, inflammation markers and hormones that might be associated with the development of metabolic disorders. "Fatty tissue is generally regarded as a hormone-producing gland; however, hormones produced in the kidneys or ovaries also have an effect on the fat cells and hence on the metabolism," said Prof. Heinz Drexel, director of the Dornbirn-based institute. Initial findings obtained in a recent study involving 2,000 patients suggest that not all hormones produced in the fatty tissue cause cardiac infarction or stroke.

Besides its research activities, the VIVIT has for many years carried out clinical studies on behalf of supraregional companies involving comprehensive patient cohorts. The major focus of the trials carried out in the academic teaching hospital in Feldkirch is on cross-sectional studies as well as prospective observations focusing on the general profile of overweight patients and the risk they run of suffering a stroke, or other diseases. In an on-going motion study involving middle-aged, adipose individuals undertaking downhill exercise, the scientists have found that physical exercise is associated with the release of fewer fats into the blood, which in turn triggers a more economic metabolism.

The victims: vessels and organs

Metabolic disorders are often associated with damage to different organs, including the liver. The correlation between liver disorders, metabolic syndrome and heart disease is another major research priority at the VIVIT. “If fatty tissue is jam-packed with fats to a degree that it needs to release the fat into the blood due to hormonal effects, it is generally the abdominal fat that is transported into the liver,” said Prof. Heinz Drexel. If a metabolic disorder causes the liver to take up more fat than can be released, the fat remains in the liver, subsequently leading to fatty metamorphosis of the liver. The measurement of liver enzymes in the blood showed that the lipid metabolism leads to defects in the liver and blood vessels, but also showed that it is not the liver that causes diseased blood vessels. “It goes without saying that this process is accelerated by the frequent consumption of alcohol as alcohol is a small fat molecule rather than a carbohydrate,” said Prof. Heinz Drexel.

The VIVIT also focuses on the investigation of the bone metabolism with regard to the development of heart disease. The researchers’ results have shown that blood disorders are associated with bone and heart metabolisms, but that the bones and the heart do not have a direct connection with each other. “This means that there might be a simultaneous risk of developing bone atrophy and arteriosclerosis, but that there is no mutual causal connection between the two diseases, a finding which goes against previous hypotheses,” said Prof. Heinz Drexel.

Focus on DNA polymorphism

In cooperation with other institutions, the VIVIT determines different key metabolites in patient plasma, the accumulation of which might lead to metabolic diseases. © VIVIT

The VIVIT also focuses on the investigation of different clinical and molecular biological parameters to gain further insights into metabolic disorders and how they develop. "We use large, well-characterised patient cohorts to analyse common variations in the genetic material, so-called DNA polymorphisms, and investigate their occurrence with intermediary phenotypes such as cholesterol or glucose values and clinical end products such as atherosclerosis or diabetes," said Dr. Axel Mündlein, head of the molecular biology laboratory at the VIVIT. In addition, in cooperation with other institutions, the VIVIT also determines a variety of key metabolites in patient plasma, the accumulation of which can lead to metabolic diseases.

In a recent genetic association study, the researchers found that DNA variations at a specific site of chromosome 1 are associated with cholesterol and angiographically determined coronary heart disease. "The association of these DNA variations with cholesterol was discovered a little while ago, but the fact that they are associated with heart disease is a new finding," explains Dr. Axel Mündlein. In addition, Mündlein and his team have recently shown that a specific DNA variation in a diabetes predisposing gene is not only associated with diabetes but also with coronary heart disease. "This finding provides further evidence for a genetic link between these two diseases," said Mündlein.

The VIVIT institute cultivates cells in order to reconstruct and better understand the generation of fatty tissue. "Over the last few years we have obtained increasing evidence that the fatty tissue not only functions as an energy store, but that it is also an endocrine organ," said Dr. Axel Mündlein further explaining that the chronic inflammation of fatty tissue is a "key process" in the pathogenesis of metabolic diseases. According to Mündlein, the fat cells of the abdominal fat tissue are insufficiently supplied with oxygen, which leads to the increased release of inflammation factors and the death of cells. Under laboratory conditions, the VIVIT institute exposes fat cells to oxygen deprivation in hypoxia chambers in order to analyse the changes in the cells on the molecular level. "We use gene chips to investigate the entire gene expression profile," said Dr. Axel Mündlein. The results are being verified with additional RNA and protein analyses and the first conclusions are expected shortly. It is already possible to conclude from the investigations that more than 1000 genes are significantly regulated.

Environmental factors as trigger

With regard to the predictability of metabolic disease and secondary diseases, the VIVIT researchers say that enormous progress has been made, especially in the field of genetics and genome-wide association studies. “However, with the exception of rare monogenetic diseases such as mucoviscidosis, the development of complex diseases such as coronary heart disease or diabetes mellitus is often influenced by several genes, each individual gene often contributing relatively little to the pathogenesis of such complex diseases,” said Dr. Axel Mündlein. Little is still known about the concrete effect of simultaneous genetic alterations that have a weak effect. Therefore, the familial predisposition to such a disease is still regarded as the surest sign that a family member runs the risk of contracting a metabolic disease from which several other family members suffer.

Genetic investigations are frequently used to confirm a suspected metabolic disease such as haemochromatosis, celiac disease or hyperlipoproteinemia. If a healthy person who does not display certain disease symptoms has the same genetic modifications as a sick person, the healthy person generally has a lower risk of contracting the disease during his or her life. “Besides predisposing genetic factors there must be environmental factors that lead to the onset of a disease,” concludes Dr. Axel Mündlein adding that no definite statements can be made on the predictability of a certain disease occurring despite the fact more is now known about the genetic influence on the pathogenesis of numerous diseases.

Further information:

VIVIT
Prof. Dr. Heinz Drexel
Carinagasse 47
A-6800 Feldkirch
Tel: +43 5522 303 26 70
Fax: +43 5522 303 75 33
E-mail: vivit(at)lkhf.at

Dr. Axel Mündlein
Tel: +43 5572 372 65 81
Fax +43 5572 372 65 84
E-mail: labor(at)vivit.at

Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/a-view-into-the-genome-provides-information-on-the-lipid-metabolism