Anti-platelet treatment for metabolically induced NASH and HCC
Mohsen Maleh Mir, Elena Kotsiliti2, Dominik Pfister2, Valentina Leone2, Carsten Deppermann3, Julia Volz3, Daniel Dauch4, Bernhard Nieswandt3, Lars Zender4, Achim Weber1*, Mathias Heikenwälder2,5 *
1Department of Pathology and Molecular Pathology, University Zurich and University Hospital Zurich; 2Institute of Virology, Helmholtz Center Munich, TU Munich; 3Rudolf Virchow Center, University of Würzburg; 4Division of Translational Gastrointestinal Oncology, University of Tübingen; 5Department Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ),5
*authors contribute equally
By utilizing a long-term choline-deficient high-fat diet (CD-HFD), we recently have established a mouse model in which CD8+T- and NKT cells interact with hepatocytes to induce NASH and eventually NASH-to-HCC transition. Several studies have shown that platelet contribute to immunopathology of liver. Our pilot study revealed that CD-HFD mouse model reveals an increased platelet number as human NASH patient. Therefore, we aim to test whether platelet activation/aggregation is a driving force for liver recruitment of CD8+T- and NKT cells during disease progression. We hypothesize that accumulation of CD8+T- and NKT immune cells in the liver is mediated by activation/aggregation of platelets and anti-platelet therapy will reduce the conditions associated with NASH, hyperlipidemia and glucose tolerance.
We are evaluating platelet deposition in NASH livers, long-term consequences of anti-platelet treatment with aspirin-clopidogrel as well as pharmacological inhibition of COX2 by sulindac and P2Y12 by Ticagrelor in the CD-HFD mouse model. Furthermore, different mouse models with genetically modified genes crucial for platelet activation/aggregation are studied. Different parameters including body weight, glucose metabolism, functioning of liver (serum ALT and AST levels), platelet phenotype, liver histology and HCC incidence are evaluated.
Aspirin-clopidogrel and Ticagrelor treatment has reduced the intrahepatic accumulation of the CD8+T- and NKT cells. All of the parameters associated with NASH, including body weight, hyperlipidemia have decreased following treatment. Interestingly, the tumor incidence has been reduced significantly. Furthermore, we have identified genes that are involved in the pathogenesis of the disease and deficiency of which protects against the conditions associated with NASH, hyperlipidemia and improves glucose tolerance.
From these experiments, we expect to unravel how less platelet activation/aggregation in the liver leads to less NASH and NASH-driven HCC under high calorie environment. Understanding these mechanisms in a preclinical model is expected to provide the basis for developing an antiplatelet therapy against NASH and NASH-driven HCC in humans.
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