High fat diet induced hepatocyte exosomes-promoted hepatic inflammation and tumorigenesis

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ABSTRACT The overall goal of this proposal is to study the role of hepatocyte exosomes in high fat diet mediated promotion of liver cancer development. Further, we will determine whether using novel edible fruit exosomes as a delivery vehicle for targetable delivery of an anti-inflammatory agent to tumor cells for treatment of liver cancer. Our preliminary data has indicated that hepatocyte exosomes are present in the peripheral blood of obese mice and obese individuals and the hepatocyte exosomes from mice fed a high-fat diet (HFD- exosomes) promote inflammatory responses and the growth of liver cancer in mouse model. These data implicate the production of hepatocyte exosomes in the inflammatory responses associated with liver cancer. Our preliminary data indicate that the HFD-exosomes carry high levels of sumoylated CSN5 (sumo-CSN5) and that the delivery of the sumo-CSN5 to immature myeloid promotes the degradation of Jak3, a process that is essential for differentiation of the myeloid cells. This pinpointed the production of the sumo-CSN5 as a critical pathogenic step in exosomes mediated Induction of inflammation cytokines. In hepatocyte cells, ErK1/2 kinase is activated by a soluble factor(s) from the supernatant of liver extracts of high fat-fed mice and causes the disassociation of Senp1 which acts as a suppressor of sumoylation of CSN5, thereby promoting the production of sumo-CSN5. This process is inhibited by curcumin, which is known to inhibit ErK1/2 activation. Therefore, we hypothesize that a high-fat diet promotes the production of exosomes with high levels of sumo-CSN5 by hepatocyte cells; that these exosomes are taken up by immature myeloid cells, resulting in sumo-CSN5- mediated immunosuppression by enhancing degradation of Jak3, and thus the promotion of tumor growth. We further hypothesize that curcumin treatment leads to the inhibition of processing of sumoylation of CSN5 in the hepatocyte cells from mice fed a high-fat diet by inhibition of ErK1/2. These hypotheses will be tested in vitro and in vivo to determine whether: (1) Sumoylated CSN5 in high-fat hepatocyte exosomes is essential for accumulation of activated iMCs and promotion of liver tumor progression; (2) The ErK1/2 signaling pathway determines the balance of desumoylation vs. sumoylation of CSN5 in hepatocyte cells and is promoted by a high-fat diet; and (3) the high-fat diet-induced hepatocyte exosome-mediated promotion of liver tumor growth is reversible by using novel edible fruit exosomes as a delivery vehicle for targetable delivery of an anti- inflammatory agent to inflammatory cells for treatment of cancer. Clinical Relevance. The data generated should identify a novel mechanism that links a high-fat diet to inflammatory and immunosuppressive responses associated with tumor development and thereby identify molecular targets for chemotherapy or chemoprevention. Demonstration of the safety of fruit exosomes-based delivery of curcumin and its targeting to inflammatory cells would be a significant step forward in the treatment of this debilitating disease.