Does BMP-9-driven fat-liver cross-talk and its actions on macrophages protect from NASH/HCC development?

• Applicants: Privatdozentin Dr. Katja Breitkopf-Heinlein; Professor Dr. Christoph Reißfelder, since 4/2024
• Subject Area: Gastroenterology ; Pathology
• Term: since 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 393225014

Bone morphogenetic protein (BMP)-9 is a secreted cytokine, belonging to the TGF-β super-family. It is constitutively synthesized in the liver and circulates with the blood stream in an active conformation. Due to increasing prevalence of obesity, non-alcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease and it is well accepted that HCC develops frequently on the basis of NAFLD. Therefore, a better understanding of the molecular mechanisms underlying malignant NASH progression is urgently needed. In the proposed follow-up study, we therefore aim at understanding how BMP-9 may protect from NASH-development and thereby finally from HCC. We and others have previously shown that BMP-9 is i.) a quiescence factor for endothelial cells and hepatocytes ii.) a mediator of inflammation including macrophage (MP) M1-polarization and iii.) associated with anti-obesity and anti-diabetes mechanisms. In support of our assumption that BMP-9 might play a role in NASH-HCC development, it was recently reported that ACVR2A, a BMP-type II receptor with affinity to BMP-9 is one of the most frequently mutated genes particularly in NASH-HCC. Our unpublished pre-works and published data from others show that increased expression of inflammatory genes in adipose tissue directly correlates with progression from NAFL-to-NASH and fibrosis. Govaere et al. showed that the lipid uptake receptor, Msr1, on Kupffer cells mediates the formation of foamy MP along with enhanced inflammation in hepatic as well as adipose tissue of mice fed an HFD. We previously showed that BMP-9 worsens liver damage in mice fed an MCD and that in MP-depleted animals, overexpression of BMP-9 was no longer effective. New, preliminary results comparing liver and fat tissue now point to the conclusion that lack of BMP-9 has also profound effects on the inflammatory status of the fat tissue. Although our BMP-9-/- mice are not (yet) obese, they already show a disturbed balance of adipokines, enhanced angiogenesis and activation of MP in adipose tissue. These data prompt us to now investigate the cross-talk between liver-derived BMP-9 and visceral fat tissue (omentum) in the context of NASH development finally leading to HCC in more detail. Our proposed project will address the BMP-9 dependent interrelation between the liver and the visceral fat tissue in vitro, using adipose-tissue-derived organoids, in mice using a transgenic line with MP-specific deletion of the BMP-9 receptor Alk1 and on a translational level, by investigating the relevance of such BMP-9 effects in human patient samples. Thereby our results will help to better understand the in vivo functions of BMP-9 and how it could be targeted for future therapies.

• DFG Programme: Research Grants
• Ehemaliger Antragsteller: Professor Dr. Nuh Rahbari, until 3/2024