Metabolic Dysfunction-associated Fatty Liver Disease: mechanisms and targets for intervention
Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) is a complex disease ranging from simple steatosis to steatohepatitis, fibrosis, cirrhosis and eventually hepatocellular carcinoma. One of the hallmarks of MAFLD is exposure to excessive amounts of (toxic) lipids, leading to lipid accumulation in hepatocytes, mitochondrial dysfunction, oxidative stress, ER stress and eventually hepatocyte injury and death. Damaged hepatocytes also impact on non-parenchymal liver cells like Kupffer cells and stellate cells leading to inflammation and fibrosis.Palmitate-induced lipotoxicity has been widely used as an in vitro model for lipotoxicity in MAFLD. Palmitate-induced toxicity recapitulates the main features of MAFLD pathology: organelle (mitochondria and ER) stress, oxidative stress and cell death. In our studies, we have shown that hesperetin, scopoletin and umbelliferone can be considered as a therapeutic strategy to alleviate these pathological phenomena and to prevent cell death in the context of MAFLD. The direct effects of these compounds on non-parenchymal cells still needs to be investigated. Our studies were mainly performed in cultured cells. Therefore, our results should be confirmed in representative in vivo models and eventually in clinical trials. Our studies with GSK3β should be extended to include the role of other targets of GSK-3β such as the Wnt pathway. Moreover, the interrelationship between GSK-3β, the PI3K/Akt/mTOR signaling pathway and autophagy should be elucidated in more detail. Finally, the role of extracellular vesicles in intercellular communication is an interesting area of research. In particular, the determination of the content of Evs and their role in the pathophysiology of MAFLD needs to be elucidated in more detail. Identifying specific components (e.g. miRNAs) that play a key role in the pathogenesis: as diagnostic markers and targets for intervention.