Current lifestyle and nutritional habits have an impact over global health, spreading the development of obesity worldwide. In this context, the liver is the main organ responsible for the maintenance of energetic and metabolic homeostasis. Added to the appearance of cardiovascular diseases, liver pathologies are also spreading worldwide. Metabolic-associated fatty liver disease (MAFLD) is estimated to affect around 25% of the global population, where the chronicity of the disease may lead to more severe hepatic disorders. MAFLD is characterized by an abnormal lipid deposition in the liver that can promote the appearance of hepatic fibrosis, and derived cirrhosis, and even liver cancer.
When lipids are accumulated, hepatocytes attempt to increase their consumption to restore the balance. However, the effort is normally not sufficient so that a pro-inflammatory stage is developed. Such inflammation is one of the main reasons for the progression of the disease to the aforementioned severe stages. The enhanced lipid consumption is accompanied by an increased mitochondrial activity, with the subsequent stimulation of the central metabolic pathway known as Krebs cycle. The interconnection existing among the different metabolic pathways links such Krebs cycle over-activity with an increased glutamine degradation to fuel it.
This is why MAFLD patents, especially the ones that develop steatohepatitis, show higher glutamate levels by an increased expression of the hepatic glutaminase 1 (GLS1) enzyme. In the study from Dr. Simón and led by Dr. Cardoso Delgado and Dr. Martínez-Chantar, the Liver Disease Laboratory (CIC bioGUNE & CIBERehd) has discovered that a siRNA-based therapy is able to diminish the Krebs cycle over-activity, decreasing the inflammation and rewiring the metabolic flux. Under the downregulation of GLS1, hepatocytes are able to synthesize phospholipids that are essential for lipid clearance in form of lipoproteins. The work sets the basis of a better understating of the metabolic abnormalities that occur during liver pathologies, and the role of the enzyme GLS1, which had been previously related with severe hepatopathies but not with MAFLD.
Link to website (Liver Disease Laboratory): https://www.cicbiogune.es/people/mlmartinez