Computer model takes us closer to treatment of our most common liver disease
Non-alcoholic fatty liver disease is the most common liver disease in the Western world. In the United States 20-30% of the population suffers from the disease, which is considered to be caused by obesity and the metabolic syndrome. The condition comprises a spectrum of pathological changes, is progressive, and can develop into cirrhosis as well as liver cancer, which in turn ultimately leads to death if not a liver transplantation is conducted.
Researchers at the department of Chemical and Biological Engineering, in collaboration with researchers at SciLifeLab in Stockholm/Uppsala, have now created a computer model of liver cells that can be used to reveal changes in the liver cell metabolism when different diseases develop. In the current study, the model was used to analyze clinical data from patients with non-alcoholic fatty liver disease. The result of the study is new knowledge about the underlying cause of the disease. This gives new opportunities, both in terms of developing new treatments as well as methods for early diagnosis of the disease.
– It was extremely exciting to use this fantastic model resource for data analysis and I am confident that this will enable more detailed analysis of liver metabolism in the future, says Dr. Adil Mardinoglu, who is first author on the paper.
– For me it was also very exciting to see the concept of metabolic modelling being applied for analysis of human disease development, says Dr. Rasmus Ågren, shared first author of the paper and who worked on this as part of his PhD study, where he developed several pioneering methods for reconstruction and analysis of detailed metabolic models.
Early diagnosis is important to prevent the disease from progressing to more serious conditions such as cirrhosis and liver cancer. However, there are no good methods for early diagnosis today. Most patients with non-alcoholic fatty liver disease have no symptoms or clinical findings typical for liver disease. At later stages of the disease, liver biopsy remains the gold standard for diagnosis, but there are severe risks associated and it is therefore avoided as far as possible. The need for new diagnosis methods is therefore great. In the current study, two novel biomarkers were identified that could potentially be used for early diagnosis through a simple blood sample.
The analysis also showed that non-alcoholic fatty liver disease is associated with serine deficiency in the liver, which was previously unknown. Since the model clarifies what has changed in the metabolism and thus causing the deficiency, the researchers can also suggest new drug targets that could potentially be used to prevent the deficiency to arise. It may also be possible to counteract the deficiency by dietary intervention, something that has worked for another medical condition caused by serine deficiency in the brain. To summarize, there is currently no efficient pharmacological or dietary treatment, and new therapeutic approaches are in great demand.
The study has been commented in Nature Reviews Gastroenterology Hepatology (link at the bottom of the page). The researchers are now in the process of building up new collaborations with research groups that can evaluate the proposed biomarkers, drug targets, and treatments in clinical trials.
In the study, a map of the human liver metabolism is presented. The map has been produced by a collaborative project between Professor Jens Nielsen’s group at Chalmers and researchers at SciLifeLab. The virtual liver map has been built from a comprehensive list of all known biochemical reactions that occurs in the human body, together with proteomics data from the Human Protein Atlas which experimentally validates the incorporated reactions. The map contains more than 7,500 reactions and 2,322 associated genes, and it represents a great resource for systems biologists working in human disorders related to liver metabolism.
This highly curated map can be used to enable interpretation of systemic effects, provide deeper insight into omics data for better understanding of the genotype–phenotype relationship and, most importantly, be used for computational modelling of the metabolism in a living liver cell. It could therefore prove to be very important for revealing the deficiencies or alterations in the metabolism of hepatocytes that can lead to complicated disorders such as hepatitis, non-alcoholic fatty liver disease (NAFLD), cirrhosis and liver cancer. These diseases are serious threats to public health and their underlying molecular mechanism for their occurrence still remains elusive.
On the basis of liver transcriptomics data of NASH patients and systems biology-based approaches, it was found that the expression of the genes involved in the biosynthesis of chondroitin sulphates (CS) are upregulated, whereas the expression of genes involved in the biosynthesis of heparan sulphates (HS) are downregulated. Hence, the blood concentrations of CS and HS were predicted to be suitable for diagnosing NASH and for the staging of NAFLD. Furthermore, the analysis showed that the NAFLD is associated with serine deficiency, which points to an opportunity to use dietary intervention to prevent development of NAFLD to NASH.
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The study has also been commented in Nature Reviews Gastroenterology Hepatology: