RESUMO
Liver fibrosis is a pathophysiological process characterized by abnormal accumulation of connective tissues in the liver caused by chronic liver injuries, in which the activation and migration of hepatic stellate cells (HSCs) play a central role. Extracellular vesicles (EVs) are a class of nanoscale, bilayer lipid enveloped vesicles secreted by almost all cells. EVs are of great interest in liver pathology because they have been found to mediate the communication between cells and regulate cellular microenvironment via horizontal transfer of their cargoes. EVs carry bioactive cargoes including proteins, lipids and RNA molecules, and are involved in the activation of HSCs during liver fibrogenesis.
RESUMO
Alcohol abuse is highly prevalent, but little is understood about the molecular causes. Here, we report that Ras suppressor 1 (Rsu1) affects ethanol consumption in flies and humans. Drosophila lacking Rsu1 show reduced sensitivity to ethanol-induced sedation. We show that Rsu1 is required in the adult nervous system for normal sensitivity and that it acts downstream of the integrin cell adhesion molecule and upstream of the Ras-related C3 botulinum toxin substrate 1 (Rac1) GTPase to regulate the actin cytoskeleton. In an ethanol preference assay, global loss of Rsu1 causes high naïve preference. In contrast, flies lacking Rsu1 only in the mushroom bodies of the brain show normal naïve preference but then fail to acquire ethanol preference like normal flies. Rsu1 is, thus, required in distinct neurons to modulate naïve and acquired ethanol preference. In humans, we find that polymorphisms in RSU1 are associated with brain activation in the ventral striatum during reward anticipation in adolescents and alcohol consumption in both adolescents and adults. Together, these data suggest a conserved role for integrin/Rsu1/Rac1/actin signaling in modulating reward-related phenotypes, including ethanol consumption, across phyla.
