Glycogen synthase kinase (GSK) 3β is a major hub in LSEC in MASH. GSK3β is a major hub in MASH mice LSECs

A kinome map was generated from liver sinusoidal endothelial cell (LSEC) phospho-proteomics. The orange arrow and dotted circle point to glycogen synthase kinase (GSK) 3β as the major hub in primary mouse LSEC on a metabolic dysfunction-associated steatohepatitis (MASH)-inducing diet.

Focus Areas

Focus areas include:

  • Lipotoxic endotheliopathy. Hepatic sinusoidal endotheliopathy is a pathological condition induced by lipotoxic stress in MASH and characterized by the structural and functional alteration of liver sinusoidal endothelial cells (LSECs). These alterations manifest as increased LSEC adhesion molecule and pro-inflammatory chemokine and cytokine expression, LSEC capillarization, and increased vascular reactivity. Dr. Ibrahim's program examines the molecular mediators and the epigenetic mechanisms that regulate lipotoxic endotheliopathy.

    The lab identified glycogen synthase kinase (GSK) 3β as the most enriched kinase and a major hub by kinome profiling of phospho-proteomics performed on LSECs isolated from mice with MASH. The goal is to identify druggable epigenetic modifiers that promote lipotoxic endotheliopathy. The lab has embraced the advances in spatial biology technology to understand the zonal mediators of lipotoxic endotheliopathy.

    The long-term goal is to identify LSEC-based therapeutic targets in MASH that abrogate the sterile inflammatory response, restore the homeostatic function of LSEC and reduce LSEC vasoreactivity.
  • Cross talk of LSECs, immune cells and stellate cells in MASH. LSECs are a platform for various immune cells, including monocytes, to establish residence in the liver. The Ibrahim lab studies the cross talk of LSECs, immune cells and stellate cells under lipotoxic conditions. The lab uses in vitro models, such as primary liver cells-derived organoids. The lab also uses sophisticated coculture systems, shear stress flow-based adhesion assays and in vivo mouse models of MASH with selective suppression of various LSEC adhesion molecules.
  • Lipotoxicity and liver inflammation. The lab examined the role of pro-inflammatory hepatocyte-derived extracellular vesicles (EVs) in MASH pathogenesis. The lab established the required technical expertise to examine the role of EVs derived from hepatocytes under toxic lipid stress in intercellular communication and liver pathobiology. The research team has demonstrated that these EVs are enriched with adhesion molecules, mainly integrin β1, which plays a pivotal role in monocyte adhesion to LSECs and liver inflammation in MASH. These experimental studies demonstrated that integrin β1 neutralizing antibody attenuated murine MASH mainly through reduced pro-inflammatory monocyte hepatic infiltration and activation. The lab is now interested in employing nanovesicles as a delivery system for cell-specific therapeutic interventions in murine MASH.