Title : Exploring the mechanism of ID1-dependent liver inflammation induced by dietary fat and a therapeutic approach to target IDs in cancer
Abstract:
High dietary fat contributes to a pathologic inflammatory response in the liver called non- alcoholic steatohepatitis (NASH), a significant risk factor for hepatocellular carcinoma (HCC). How high dietary fat leads to inflammation and ultimately HCC is poorly understood. We have recently shown that the dominant-negative transcription factor ID1 is upregulated in the resident macrophages of the liver (Kupffer cells, KCs) in response to two independent dietary protocols that induce steatosis (HFFD C HFFD+ carbon tetrachloride). Accordingly, liver biopsies from NASH patients showed strong ID1 nuclear staining, which co-localized with the KC-specific marker CD68, whereas liver biopsies from patients with NAFLD, a pathological condition prior to the severe inflammatory response were negative for ID1.Thus, ID1 expression in KCs correlates with disease progression from NAFLD to NASH. While the pathogenesis of high dietary fat- induced inflammation is poorly understood, determining the mechanism whereby loss of ID1 in KC offers protection against inflammation will shed light on the underlying biology of this disease. In addition, utilization of our recently reported ID degraders (AGX51 and AGXA) in nanoparticle formulations may offer a novel therapeutic approach to the treatment of these pathologies. We may also want to explore the possibility of targeting ID1-expressing cancer stem cell like populations in aggressive cancers which often resist standard chemotherapy treatments and often later contribute to a recurrence.
