Lipid-induced toxicity promotes metabolic dysfunction-associated steatohepatitis pathogenesis through release of S100A11-extracellular vesicles

• Applicant: Dr. Jasmin Weninger
• Subject Area: Gastroenterology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 567015953

Metabolic dysfunction-associated steatohepatitis (MASH) is the most prevalent chronic liver disease worldwide, and its incidence is rising alongside global metabolic disorders. Currently, there are no approved therapies for MASH, which results in progressive liver inflammation and damage. This pathology is driven by complex interactions between stressed hepatocytes and innate immune cells. Although this cell-to-cell communication is critical for disease progression, its underlying mechanisms remain largely elusive. This research project focuses on unraveling these mechanisms with a special emphasis on the S100 calcium binding protein A11 (S100A11). S100A11 is upregulated by hepatocytes in MASH. Lipotoxic hepatocytes release S100A11 containing extracellular vesicles (EVs) which activate macrophage receptor for advanced glycation endproducts (RAGE) signaling. Inhibition of S100A11 decreases macrophage-associated hepatic inflammation in MASH. In this proposal, it is planned to examine the micro-environmental hepatocyte-to-macrophage communication mediated by S100A11-EVs and RAGE as a potential key mediator of proinflammatory monocyte-derived macrophages accumulation, to advance the incomplete understanding of this cell-to-cell crosstalk in MASH. Based on these original preliminary data, the central hypothesis was formulated that lipotoxic hepatocytes release S100A11-EVs which activate a subset of proinflammatory RAGE expressing intrahepatic macrophages promoting MASH pathogenesis. The questions generated to address this inflammatory cell-to-cell communication in MASH are: i) how does IRE1α/XBP1 signaling upregulate S100A11 gene transcription and packaging into EVs? ii) What is the mechanism and consequence of RAGE activation by EVs? iii) Can cell-to-cell communication between S100A11-EV and RAGE be interrupted to decrease hepatic inflammation? Using different established and well characterized in vivo an in vitro models our special aims prove as follows: Aim 1 will elucidate the mechanism of S100A11 enriched EVs are releases by lipotoxic hepatocytes by IRE1α-XBP1 driven transcriptional upregulation of S100A11 via binding to and recruiting the histone acetylating factor P300 to an enhancer region and by selective cargo sorting of S100A11 into lipotoxic EVs. Aim 2 will examine how RAGE activation in a subset of macrophages by lipotoxic EVs occurs, namely via the generation of signal-competent RAGE receptor oligomers, which in turn leads to the accumulation of a subset of proinflammatory RAGE-expressing macrophages in the liver. Ultimately, this research aims not only to deepen our understanding of the mediators of cell-to-cell communication between hepatocytes and macrophages under lipotoxic conditions but also identify potential therapeutic target in MASH.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professorin Dr. Harmeet Malhi