HARMEET MALHI: My name's Harmeet Malhi. I am the associate chair for research for the Division of Gastroenterology and Hepatology. We really want to ask and answer fundamental mechanistic questions of how and why the liver is injured in NASH. One of these is to demonstrate that the toxicity of lipids or lipotoxicity leading to the cell death of hepatocytes is a key mediator of NASH.

A second set of observations pertains to examining how ER stress activates what we call a de novo ceramide synthesis pathway in the liver. This leads to the formation of these tiny, tiny particles that cells release. We call them extracellular vesicles. We've gone on to show that these EVs the hepatocytes are releasing as a consequence of ER stress are pro inflammatory and they can attract macrophages into the liver [INAUDIBLE] promoting liver inflammation.

So one of the studies we've done has demonstrated that a lipid mediator, a molecule called sphingosine 1-phosphate on these extracellular vesicles communicates with the immune cells through a set of receptors. And we can block this or the pharmacological inhibitor, a small molecule, to show that we can improve NASH. And our hope is to be able to identify the patients that, say, may benefit from inhibitors of the S1-P, or the sphingosine 1-phosphate signaling pathway that our lab has identified. And we want to be able to treat NASH at a time before patients develop advanced fibrosis or cirrhosis. Being visible in the field nationally and internationally, I'm able to attract phase three clinical trials to Mayo Clinic for NASH patients, which are really necessary to be able to find the best drugs and targets for NASH therapy.