Targeting non-alcoholic fatty liver disease

The Lipids & Liver group at the UPV/EHU-University of the Basque Country is stepping up research into liver diseases that affect a significant proportion of the population

  • Erreportajeak

First publication date: 06/07/2018

One of the lines of research of the UPV/EHU's Lipids & Liver group, which focusses on the mechanisms involved in the development and progression of non-alcoholic fatty liver disease, is achieving significant advances in a range of aspects; these include the identification of proteins that alter the metabolic pathways in the development and progression of liver disease, and even cancer, and the seeking of targets to enable the disease to be reversed.

Targeting non-alcoholic fatty liver disease
Researchers of the UPV/EHU's Lipids & Liver group. Caption: Egoi Markaida. UPV/EHU.

According to the latest figures, non-alcoholic fatty liver disease affects 30% of the general population, and this percentage rises to between 70% and 80% in certain risk groups, such as obese patients, patients with diabetes, etc., due to the fact that the latter is linked to metabolic diseases.  The disease begins with a simple build-up of fat or lipid in the liver which in principle may be benign but which in some patients may progress and lead to hepatitis, steatohepatitis, because of its inflammation, and this is a risk factor for developing hepatic cirrhosis and even liver cancer. Right now, there is no specific treatment for this disease, and owing to the current high prevalence of obesity and diabetes, it is forecast that within a few years liver cancer cases caused by this fat storage could soar, as could the number of transplants caused by non-alcoholic steatohepatitis.

The Lipids & Liver research group in the department of Physiology at the UPV/EHU’s Faculty of Medicine and Nursing is working to find out what mechanisms are involved in the development and progression of liver diseases, and mainly the mechanisms related to alterations linked to lipid (fat) metabolism. Specifically, one of the group’s lines of research, which focusses on the study of non-alcoholic fatty liver disease, is involved in research that aims to “find out why the disease develops in some patients and not others; to find evolution markers that can provide us with a prognosis as to which patients are going to develop the disease; and to find not only hepatic markers (that can be obtained through biopsy) but also serum markers, which by means of simple blood tests can say which phase the patient is in”, explained Dr Patricia Aspichueta, head of the line of research.

The liver is the metabolic centre of the whole body

Basically, the members of the research group are focussing on the study of lipid metabolism in the liver, in other words, on the chemical reactions in which they are formed or consumed. To do this, they work with animal models in which a gene has been silenced and to which different diets and treatments designed to induce the disease are given, and once a target in the animal model has been confirmed or identified, they proceed to validate it in human samples. What is more, they also work with in vitro or cell models, “because there it is easier to find out in which cell the metabolism has been damaged, modified or altered, we can play around with different drugs, different inducers, and it is easier to silence specific metabolic pathways, etc.”, explained Aspichueta.

The members of the group are studying different molecules or targets involved in various liver disease processes. Aspichueta specifies some of the pathways that they have open in the research group: “Firstly, we want to identify the proteins that alter the metabolic pathways and which supply the liver with more lipid. We want to find out why this lipid store forms, and why the store causes the disease to progress to phases such as cancer, even. It is important to know which players are involved in these processes to be able to silence them and see if the disease is reversed.” They are also exploring the involvement of lipids in liver regeneration, “a hugely important perspective with respect to patients who have had a portion of their liver removed, because the liver is the only organ that regains its normal size”. In another of the studies they are exploring “how the liver controls adipose tissue, and how by modulating liver function we can get animals to lose weight”.

Aspichueta confirms that they have found “an important therapeutic target that modulates the metabolism and the progression of the disease”. They have induced the development of liver cancer associated with obesity in animal models in which this protein has been silenced and “we have seen that the animals do not develop the disease at all: neither liver cancer nor the fat store. It’s amazing,“ said the doctor. Now “we are working on human samples of non-alcoholic fatty liver disease to validate the involvement of these proteins in human pathology”. The researchers are aiming to find targets that control several metabolic pathways at the same time, “because the metabolic alteration does not take place in a single pathway, rather a decompensation takes place, the metabolism becomes unbalanced and various pathways are affected,” she concluded. The liver is the metabolic centre, and if we control the liver we can control many disorders associated with this liver disease”.

Additional information

The Lipids & Liver research group has been recognised as a Consolidated Group by the Department of Education of the Basque Government since 2007. Its research work relating to the Physiopathology of Lipid Metabolism comes within the strategic Health and Life Quality line of the Spanish Ministry of the Economy and Competiveness and of the Basque Government, in the sphere of the Euskampus biomedicine and healthy Ageing and life quality.

The group works in close collaboration with various research groups at the UPV/EHU as well as external ones with which they have had numerous publications in various scientific journals. The group is part of the Biocruces Institute for Health in which it broadens its research to the disorder in humans. It also collaborates with CIC bioGUNE, the University of Santiago de Compostela, other groups in Madrid, the Hospital of Valdecilla (Santander), as well as with the University of South Carolina and Yale University. It also works with an American pharmaceutical company in the quest for treatment targets.