A Deep Dive into the Hippocampal Proteome in a Rat Model of Hepatic Encephalopathy Unveils the Role of FAK1 and Tetraspanins in its Pathogenesis

Abstract

Abstract Hepatic Encephalopathy (HE) is a debilitating neurological disorder associated with liver failure, characterized by impaired brain function. This study aimed to elucidate the molecular underpinnings of HE and identify potential therapeutic targets. A model of moderate HE was induced in rats using thioacetamide, simulating the liver damage observed in patients. We employed LC-MS/MS-based label-free proteomics to quantitatively profile hippocampal proteins, identifying 2175 proteins, 47 of which exhibited significant alterations in the HE condition. Utilizing Metascape, a network analysis tool, we discovered that biological pathways integral to brain function, including gliogenesis, modulation of chemical synaptic transmission, astrocyte differentiation, regulation of organ growth, and response to cAMP, myelination, synaptic function, were disrupted during HE. The STRING database further elucidated protein-protein interaction patterns among the differentially expressed proteins. Our findings highlight Focal Adhesion Kinase 1 (FAK1) and its associated tetraspanins (Tetraspanins 2 and CD9) as key contributors to the neurological dysfunction observed in HE. Additionally, we noted alterations in cellular morphology and neuronal arborization in the hippocampal neurons of HE rats, suggesting these proteins influence synaptic communication and memory storage. This study provides novel insights into the molecular mechanisms driving HE and paves the way for identifying novel therapeutic targets for improved disease management.