LIPID MEDIATORS IN STELLATE CELL ACTIVATION AND FIBROSIS DEVELOPMENT

• Applicants: Privatdozentin Dr. Vasileia Ismini Alexaki, since 11/2024; Dr. Mario Brosch; Professorin Dr. Maria Fedorova
• Subject Area: Gastroenterology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 531079344

Genetic factors substantially influence the risk of NAFLD development. Genome wide association studies (GWAS) have identified several genes with single nucleotide polymorphisms (SNP) to be associated with NAFLD, including membrane bound O-acyltransferase domain containing 7 (MBOAT7), an enzyme involved in metabolism of phosphatidylinositol lipids. The MBOAT7 rs641738T risk variant, a loss of function mutation, is associated with fibrosis development during NAFLD. Interestingly, MBOAT7 mRNA expression is suppressed in livers of obese humans even in the absence of the MBOAT7 rs641738T risk variant and in livers of obese wild type rodents, suggesting that obesity may directly regulate hepatic MBOAT7 levels. Therefore, hepatic-MBOAT7 activity is suppressed by obesity and by the presence of the MBOAT7 rs641738T risk variant. Hepatocyte-specific MBOAT7 deficiency in mice exacerbates fibrosis development without affecting inflammation, in a model of diet-induced NAFLD. Moreover, bioactive lipid mediators, specifically lysophosphatidylinositol (LPI) and lysophosphatidic acid (LPA), are upregulated in the livers of individuals carrying the MBOAT7 rs641738T risk variant and this upregulation correlates with the presence of fibrosis. Due to the accumulating evidence linking obesity-induced hepatic MBOAT7 downregulation with the development of liver fibrosis, which is also associated with the hepatic accumulation of bioactive lipids, here, we will elucidate the molecular details of the mechanisms by which MBOAT7 modulates fibrosis development in NAFLD. Specifically, we hypothesize that MBOAT7 downregulation -either genetically or induced by obesity - triggers the profibrogenic crosstalk between hepatocytes and hepatic stellate cells (HSC) via LPI and/or LPA and its receptors. Elucidating Mboat7/LPI/LPA-mediated cell-cell communication in NAFLD-fibrogenesis may pave the way for novel therapeutic interventions. The following aims will be addressed: 1. Investigate the hepatocyte-HSC profibrogenic crosstalk via lipid mediator LPI and its receptor in genetic and NASH diet-induced MBOAT7 downregulation. 2. Investigate the importance of autotaxin (ATX) in generating LPA from LPI in HSC activation and fibrosis development during genetic and obesity-induced MBOAT7 downregulation. 3. Investigate LPA (derived from LPI) and its receptor LPAR1 in HSC activation and fibrosis development during genetic and obesity-induced MBOAT7 downregulation. The findings will identify the exact molecular players and thus the underlying mechanisms, especially the lipid signaling pathways that promote the MBOAT7-dependent cellular crosstalk that leads to fibrosis development during NAFLD and potentially identify a druggable pathway for fibrosis.

• DFG Programme: Research Grants
• Ehemalige Antragstellerin: Pallavi Subramanian, Ph.D., until 11/2024