Siberian Federal University Discover Mutations Contributing To The Development Of Liver And Kidney Diseases
SibFU scientists have analysed the role of genetic factors in the development of non-alcoholic fatty liver disease (NAFLD). The experts proved that, in addition to the widely studied mutations of rs738409 PNPLA3 gene, breakdowns of TM6SF2 and MBOAT7 genes (occurring together or separately) also inhibit lipid metabolism in the liver. The female hormone estrogen is probably able to protect liver cells from fatty disease and malignant degeneration. This explains the increased risk of NAFLD in men and the low risk in women. The scientists will have to figure out how proteins — participants in fat metabolism — affect the state of the liver in NAFLD.
Non-alcoholic fatty liver disease, also known as fatty hepatosis, affects more than 30% of the population. The main cause of this non-communicable disease is obesity which leads to a malfunction of metabolic processes and the accumulation of fat in liver cells — hepatocytes. This excess fat can provoke inflammation of the liver — steatohepatitis. The inflammation, in turn, damages liver cells and causes fibrosis which can lead to serious diseases. The most dangerous consequences are cirrhosis and hepatocellular carcinoma — a type of liver cancer.
“The emergence and development of NAFLD is partly influenced by lifestyle and nutrition pattern. Recent studies, however, have shown that polymorphisms of various genes associated with the absorption of fats play an important role in the development of this disease. We have analysed and systematized the data of publications over the past 10 years devoted to the molecular and biochemical aspects of the influence of such polymorphisms on the liver condition,” said Daria Lagutinskaia, co-author of the research, post-graduate student of the School of Fundamental Biology and Biotechnology.
Gene polymorphism is the result of mutations occurring in living organisms. Hereditary polymorphism ensures the adaptability of organisms to various environmental conditions. But there is often a price to pay for such variations of genes, for example, predisposition to certain diseases.
Daria Lagutinskaia noted that the contribution of rs738409 polymorphism of PNPLA3 is widely described in both foreign and Russian studies, but the polymorphisms of MBOAT7 and TM6SF2 and their effect on non-alcoholic fatty liver disease have been studied significantly less. In particular, it is necessary to find out how these polymorphisms manifest themselves in people of different ethnicity and age.
“The PNPLA3, TM6SF2 and MBOAT7 gene polymorphisms have various effects on the human body. First of all, they influence the structure of proteins, in particular, adiponutrin and LPIAT. As a result of the destructive effect, these proteins cease to work correctly, and fats begin to accumulate excessively in liver cells. Interestingly, such breakdowns affect negatively not only the condition of the liver but also the functioning of the kidneys. The most severe consequences can be caused by the polymorphism of rs738409 PNPLA3 genes — the changes in this gene provoke an increased body mass index and hepatic obesity. Estrogen in women is likely to reduce the negative impact caused by this mutation, but men do not have such protection, so they are more susceptible to NAFLD,” noted Daria Lagutinskaia.
According to Olga Smirnova (Doctor of Medical Scienc, professor of the Department of Medical Biology at SibFU), the rs738409 polymorphism is able to influence the development of fibrosis, and later cirrhosis in patients with NAFLD. People with this mutation have an increased risk of hepatocellular carcinoma, as well as death from liver diseases. And in general, such polymorphism is associated with an increase in overall mortality in the population.
“According to the studied data, mutations of PNPLA3, TM6SF2 and MBOAT7 negatively affect (individually and collectively) fat metabolism in the liver and its regulation. However, there are some nuances. For example, the association of TM6SF2 gene polymorphism with the development of NAFLD is confirmed in European and Asian populations, but in Latin Americans, for example, Brazilians, this relationship is not so obvious. And if the polymorphism of MBOAT7 in children from the Caucasian population was associated with an increased level of insulin and reduced sensitivity to it, as well as with a large percentage of liver fat, then this relationship is not traced in children from Latin American and African populations. The combined effect of polymorphisms of TM6SF2 and PNPLA3 is more destructive to the organism than these mutations individually. We also have to study in more detail the work of proteins involved in lipid metabolism to find out how they affect the state of the liver in NAFLD,” coccluded Olga Smirnova.