GI highlights from the literature

Abstract

BASIC SCIENCE Targeting Notch to prevent inflammation-related fibrosis in non-alcoholic steatohepatitis (NASH) Yu J, Zhu C, Wang X, et al. Hepatocyte TLR4 triggers interhepatocyte Jagged1/Notch signalling to determine NASHinduced fibrosis. Sci Transl Med 2021; 13599: eabe1692. doi: 10.1126/ scitranslmed.abe1692. NASH remains an enormous clinical problem with limited medical therapies to prevent endstage liver disease and cancer. Emerging data have suggested a role in the socalled Notch intercellular signalling pathway in NASHrelated fibrosis. To examine this further, Yu et al combined analysis of human tissue and mechanistic preclinical mouse studies. First, by retrospectively examining clinical trial data, they observed that the Notch ligand Jagged 1 (Jag1) was the only Notch pathway component that differed between those who responded to trial therapy (pioglitazone or vitamin E) versus nonresponders, an observation supported by an independent NASH cohort. In a mouse model, they confirmed zonal hepatocellular Jag1 expression with dietary induced NASH. Using hepatocytespecific knockout of the Jag1 gene, they prevented juxtaposed hepatocytes activating the Notch pathway, reducing both stellate cell activation and fibrosis deposition. Conversely, overexpressing Jag1 in hepatocytes resulted in increased fibrosis once mice were fed a NASHinducing diet. Using a Jag1 promoter reporter, they showed that inflammatory signalling from nuclear factor kappalightchainenhancer of activated B cells and Tolllike receptor 4 directly activated this process. Translational therapy, using an antisense oligonucleotide to prevent Jag1 activity in hepatocytes, was tested in mice. This was not only well tolerated and reduced Jag1 and Notchpathway activation but also reduced fibrosis both in early and established disease. It remains unclear if these studies in shortterm preclinical models will be translatable to human and whether they will impact on cirrhotic disease and other complications such as hepatocellular carcinoma but they provide an exciting step towards a novel therapy for both NASHdisease treatment and prevention.