Liver sinusoidal endothelium ultrastructure in health and MASH
Scanning electron microscopy images show fenestrated liver sinusoidal endothelium in healthy mice and capillarized endothelium with loss of fenestrae and acquisition of basement membrane in mice fed a metabolic dysfunction-associated steatohepatitis (MASH)-inducing diet.
Focus areas
Learn more about the lab's focus areas.
Lipotoxic endotheliopathy
Hepatic sinusoidal endotheliopathy is a pathological condition driven by lipotoxic stress in metabolic dysfunction-associated steatohepatitis (MASH). It is defined by structural and functional alterations in liver sinusoidal endothelial cells (LSECs), including increased expression of adhesion molecules, upregulated pro‑inflammatory chemokines and cytokines, LSEC capillarization, and heightened vascular reactivity.
Dr. Ibrahim's lab investigates the molecular pathways and epigenetic mechanisms underlying these lipotoxic injuries. Kinome profiling of phospho‑proteomics from LSECs isolated from MASH mouse models identified glycogen synthase kinase (GSK) 3β as the most enriched kinase and a central regulatory hub. This work supports the ongoing effort to identify druggable epigenetic modifiers that drive lipotoxic endotheliopathy. The lab also leverages advances in spatial biology to delineate the zonal mediators contributing to this endothelial dysfunction.
The overarching goal is to develop LSEC‑targeted therapeutic strategies for MASH that suppress sterile inflammation, restore endothelial homeostasis and reduce aberrant 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 in MASH pathogenesis. The lab established the required technical expertise to examine the role of extracellular vesicles derived from hepatocytes under toxic lipid stress in intercellular communication and liver pathobiology.
The research team has demonstrated that these extracellular vesicles 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.
The lab is investigating ferroptosis as an immunogenic cell‑death mechanism in MASH and identifying ferroptosis suppressors that can be selectively delivered using siRNA technology and lipid‑based nanoparticles. This strategy aims to develop therapeutic strategies to attenuate the inflammatory and profibrogenic responses in MASH.