NASH-promoting stress kinases

Nonalcoholic steatohepatitis (NASH) has become a significant public health problem lacking effective pharmacotherapy. Hence, a better understanding of the molecular and cellular mechanisms involved in the pathogenesis of NASH development and progression may facilitate identification of specific therapeutic targets. Our studies to date have explored different stress kinases, including glycogen synthase kinase and mixed lineage kinase 3 (MLK3), showing that the blocking of these kinases has beneficial effects in our in vitro and in vivo NASH models.

Lipotoxic hepatocytes derived extracellular vesicles and liver inflammation

The laboratory has observed that lipotoxic hepatocytes, through a mixed lineage kinase 3 (MLK3)-dependent mechanism, release CXCL10-enriched chemotactic extracellular vesicles (EVs) that promote monocyte-derived macrophage (MOMF) trafficking to the liver and inflammation in NASH. Moreover, lipotoxic hepatocyte-derived EVs are enriched with integrin β1, which enhances MOMF adhesion to liver sinusoidal endothelial cells and promotes the inflammatory process in the NASH liver. These observations are conceptually innovative and clinically significant in implicating EVs as a link between hepatocyte injury and hepatic inflammation. We have established the required technical expertise to examine the role of EVs in intercellular communication and liver pathobiology.

Perinatal nutritional reprogramming of the epigenome and NASH development in offspring

In the United States, more than 60% of women of childbearing age are either overweight or obese, and maternal obesity has been recognized as an important factor in the development of NASH in offspring. Dr. Ibrahim's lab has examined the role of an obesity-induced diet introduced at the time of conception in nutritional reprograming of the offspring epigenome leading to an accentuated murine nonalcoholic steatohepatitis (NASH) phenotype in the offspring. This process is mediated mostly by epigenetic reprograming in utero through alteration of the methylome and subsequently the transcriptome, provoking severe liver fibrosis. Hence, our ultimate goal is to identify epigenetic modifiers as potential therapeutic targets for a subset of patients with early-onset NASH.

Endotheliopathy in NASH

Obesity-induced NASH is likely associated with hepatic endotheliopathy characterized by enhanced liver sinusoidal endothelial cell (LSEC) expression of adhesion molecules, mainly vascular cell adhesion molecule 1 (VCAM1), that enhance monocyte adhesion and liver inflammation. LSECs serve as a platform for various immune cells, including monocytes, to lodge in the liver. The laboratory is interested in examining whether pharmacological inhibition of these adhesion molecules is beneficial in abrogating the sterile inflammatory response in NASH.