Overview

The Lipotoxicity and Liver Inflammation Laboratory led by Samar H. Ibrahim, M.B., Ch.B., investigates mechanisms of liver injury and inflammation in nonalcoholic steatohepatitis (NASH). The ultimate goal of Dr. Ibrahim's work is to better understand the cellular and molecular mechanisms involved in NASH pathogenesis and identify potential therapies to prevent NASH from progressing to irreversible end-stage liver disease.

Using in vitro and in vivo models of NASH, the lab examines the role of various stress kinases, including mitogen-activated protein kinases (MAPKs) — namely, mixed-lineage kinase 3 (MLK3) — in NASH pathogenesis. Recent data from the lab demonstrated that MLK3 pharmacological inhibition attenuates murine NASH.

The laboratory is studying the role of proinflammatory hepatocyte-derived extracellular vesicles (EVs) in NASH pathogenesis. We have established the required technical expertise to examine the role of EVs derived from hepatocytes under toxic lipid stress in intercellular communication and liver pathobiology.

Recent advances by the lab include the discovery of the chemotactic ligand CXCL10 as an EV functional cargo. Interestingly, CXCL10 enhances the trafficking of monocyte-derived macrophages to the liver in NASH, and CXCL10 knockout mice are relatively protected against NASH. Furthermore, 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 and liver inflammation in NASH. Our experimental studies demonstrated that integrin β1 neutralizing antibody attenuated murine NASH mainly through reduced proinflammatory monocyte hepatic infiltration and activation.

Dr. Ibrahim and her team are also interested in examining the impact of perinatal exposure to an obesity-inducing diet (OID) on the development of nonalcoholic fatty liver disease in offspring and its progression to the inflammatory and fibrosing form, NASH. Recent findings from our lab have defined a role of the nutritional reprograming of the offspring epigenome induced by in utero and early-life exposure to an OID in NASH pathogenesis.

At present, we have an ongoing research project aimed at understanding the mechanism of hepatic endotheliopathy in NASH, a condition characterized by increased adhesion molecule expression on the liver sinusoidal endothelium, increased monocyte adhesion propensity and liver inflammation. Our ultimate goal is to identify therapeutic targets to attenuate hepatic endotheliopathy in NASH.

Our research team is highly collaborative and dynamic; we strive to implement state-of-the-art and cutting-edge technology in answering clinically relevant research questions, with high potential to translate that knowledge into effective treatment.

The Lipotoxicity and Liver Inflammation Laboratory is part of Mayo Clinic's Center for Cell Signaling in Gastroenterology (C-SiG), and is mainly funded by an R01 grant through the National Institutes of Health, NIDDK 1R01DK122948-01.

About Dr. Ibrahim

Dr. Ibrahim is a pediatric transplant hepatologist and a physician scientist. Her primary research focus is on the molecular and cellular mechanisms underlying the pathogenesis of NASH. Her aim is to identify predictive biomarkers and develop novel therapeutic strategies to prevent the progression of NASH to end-stage liver disease. Dr. Ibrahim is also an assistant professor of pediatrics and an assistant professor of physiology at Mayo Clinic's campus in Rochester, Minnesota.