The prevalence of obesity and type II diabetes mellitus has increased in recent decades, becoming a global and priority health problem. These diseases are associated with multiple metabolic risk factors and an excessive accumulation of lipids in the liver; in fact, about 70-80% of these patients develop non-alcoholic fatty liver disease (NAFLD), now also known as metabolic fatty liver disease (MAFLD). It is the most common cause of chronic liver disease in Western countries and it is estimated that by 2030 it will become the leading cause of liver transplantation. It is a complex disease that does not progress in all patients in the same way. Depending on the factors that converge in each individual, its progression may be favored. MAFLD encompasses a variety of pathological conditions, from noninflammatory hepatosteatosis (NAFL) to steatohepatitis (NASH), characterized by hepatosteatosis, inflammation, and ballooning of hepatocytes. NASH triggers the development of fibrosis, cirrhosis, and / or hepatocellular carcinoma (HCC). Around 2-3% of the general population suffers from NASH and its incidence is higher in patients with obesity or diabetes (15-20%). Mortality in NASH is frequently associated with cardiovascular disease and an increased risk of cancer. Therefore, it seems essential to make a reliable diagnosis that allows us to identify patients with NASH, the "gold standard" test for diagnosis being liver biopsy. However, the risk involved in this test, together with the heterogeneity in the interpretation of the results, makes it necessary to develop standardizable non-invasive diagnostic systems. One of the objectives of this project is being able to identify serum biomarkers that make it possible to discern NAFL from NASH and even different subtypes of NASH. In turn, analyzing the viability of certain metabolic mediators as possible therapeutic targets for the disease is another of the main objectives.

Obesity and MAFLD, despite being closely related, are two independent risk factors for the development of liver cancer. Although the natural history of MAFLD may include the development of hepatocellular carcinoma (HCC), only a small percentage of patients develop it. However, the high prevalence of MAFLD and obesity have caused a rapid increase in cases of HCC of metabolic origin, making it the most common liver cancer worldwide and the third in associated mortality. Along with HCC, other liver cancers such as intrahepatic cholangiocarcinoma (iCCA) and metastases from extrahepatic cancers, such as colorectal (CRC), have seen an increased incidence, mainly associated with obesity and / or MAFLD.

The development of cancer is associated with profound alterations not only at the genomic and transcriptional regulation level, but also at the level of energy metabolism, in general, and that of lipids, in particular; a fact that it shares with liver disease. Through this project, the “Lipids & Liver” group suggests that compensatory metabolic reprogramming could be considered as an adjunct to treatment.

Currently, drug-induced liver injury (DILI) is one of the main causes of both acute and chronic liver damage. Due to this damage, liver regeneration is activated. During liver regeneration, which is also activated during MAFLD or in the development and progression of cancer, an accumulation of large amounts of lipids, mainly triglycerides (TGs), occurs in the cytoplasm of hepatocytes. This phase occurs, in the case of transient regeneration, between 12-36 hours from the beginning of the regenerative process and tends to reverse in the following 12 hours. This reversal is linked to the consumption of lipids by the hepatocyte itself to drive the regenerative process, consuming TGs to obtain metabolic energy and to obtain lipids from the plasma membrane.
Liver damage caused by drugs is characterized by oxidative stress generating large amounts of oxidative radicals (ROS) associated with alterations in lipid metabolism, among others. The “Lipids&Liver” group has extensive experience in the study of liver regeneration processes and the involvement of lipid metabolism in this process. Therefore, this project aims to investigate, on the one hand, the role of the E2F family of transcription factors and some of its targets in drug-induced liver damage, and the deregulation of lipid metabolism associated with the regenerative process coupled to hepatic injury.

The objective of lipidomics is the definition, on a large scale, of lipidomas in relation to their biological and environmental conditions. As a representation of the molecular phenotype, the lipidome not only reflects the activity of biological systems but also structural aspects of them. Advances in the definition of lipidomas have been based on the development of mass spectrometry (MS) techniques. Along these lines, the “Lipids & Liver” research group has made a crucial contribution to the creation and development of the Lipidomics unit of the UPV / EHU SGIker. This technological infrastructure provides capacities to respond to numerous questions of a biomedical nature by various research groups that have required and will require new technological approaches. In parallel, the implementation of computerized methods (deep learning) that allow the processing of data derived from various omics, will enable its structuring in protocols applicable to personalized diagnosis.

One of the areas that has given the greatest impetus to lipidomics in the field of human health research is the discovery of biomarkers. It is currently considered an essential tool for the development of medical diagnostic capabilities. It is an area of ​​clear transfer potential, but that requires, to complete the cycle between research and application, an increase in the critical mass of resources, including new tools for the study of lipidomics, and of knowledge, through the study of lipidomic changes. as a trace of pathological alterations.

Our exposure to anthropogenic chemical pollution is the world's leading environmental cause of disease and premature death. We are facing a serious but still uncertain threat with consequences that extend beyond our own exposure, since future generations can inherit that predisposition and risk. We are still beginning to understand the keys of the exposome, environmental exposure, in human health, as well as its consequences in the form of an increased risk of developing certain diseases, and among them, metabolic disorders such as obesity, diabetes and liver syndromes stand out.

Understanding the conjunction formed by genetics, lifestyle, and environmental factors is essential to address the global epidemic of metabolic disorders. In recent decades, the main determinants of genetic and epigenetic origin of these diseases have been uncovered. Likewise, important findings have been offered on the connections between metabolic reactions that seem to play an important role in the pathophysiology of these diseases. However, we are still a long way from being able to predict individual risk of developing the disease. At this time, the exposome is the one with the most vague knowledge within the equation "phenotype equals genotype plus environment" and is key to being able to predict and thus prevent the impact of exposure throughout a lifetime to many and diverse mixtures. complex of chemical compounds.

In this line of research, the objective is to advance in the development of methodologies based on mass spectrometry to identify proteins that function as a target for chemical compounds, with special attention to compounds that alter metabolism (MDCs).