Chronic liver diseases associated with obesity and alcohol (LIVDISEASES)

To this aim, we mainly focus on:

1. the establishment of a cohort of well-characterized patients with ALD and MASLD. We have already established cohorts of morbidly obese patients and alcoholic patients with biopsy-proven MASLD/ALD, complete biological and clinical data and blood, DNA and liver samples. Patients with ALD or MASLD from hepatic steatosis to HCC are currently included in a new cohort.
2. the search for actors involved in the progression of these chronic liver diseases through Omics studies. Only a group of miRNA/genes/pathways with modified expression levels in patients with steatohepatitis will be further studied.
3. the search for noninvasive scores to predict fibrotic MASH. We mainly develop new scores based on simple clinical and biological criteria using an artificial intelligence approach. Identification of new markers via our omics research will feed our databases. External validation of the proposed models will be performed by our national and international partners.

We mainly focus on osteopontin, hyaluronan, and CD44, which are co-overexpressed in human and mouse MASLD/ALD and are part of a common network. A better understanding of their combined role in liver inflammation may provide novel tools for diagnosis and for therapeutic strategies. This project is conducted via multidisciplinary approaches combining omics, transgenic mouse models, novel therapeutic approaches targeting CD44 and a large cohort of human samples to gain a comprehensive understanding of MASLD/ALD progression.

In this context, our work focuses on the contribution of innate lymphoid cells (ILC) in the development of MASLD. Specifically, we focus on natural killer (NK) cells and type 1 helper ILCs, two key players in the regulation of inflammatory and metabolic responses (Luci et al., 2009, Vivier et al., 2018, Luci et al., 2021). Moreover, it is now clearly accepted that the functions, survival and differentiation of these cells are finely controlled by metabolic pathways (glycolysis, oxidative phosphorylation, etc.) (Makowski et al., 2020). Given the growing interest in the role of NK cells in metabolic disorders and particularly in MASLD (Luci et al., 2019; Bourinet at al., 2023), understanding their metabolism in order to better exploit their effector functions is of fundamental and translational interest to open innovative and promising therapeutic perspectives for MASLD.

We recently highlighted that the SYK-3BP2 pathway, by regulating LPS-TLR4 responses in hepatocytes and liver macrophages, contributes to the onset of NASH. The hepatic expression of SYK is also upregulated with MASH and correlates with liver macrophages in biopsy-proven MASLD patients (Cell Mol Gastroenterol Hepatol. 2022;13(1):173-191). Since SYK also regulates hepatic stellate cell activation, liver fibrosis and MASLD progression to HCC by regulating myeloid cells, our next goals will be:

• to better decipher SYK-dependent signaling pathways regulating macrophage functions in our models of chronic inflammation.
• to preclinically evaluate how targeting of SYK in specific liver cells and by pharmacologic inhibitors improves the pathogenic chronic inflammation in mouse models of fibrotic MASH and MASH-driven HCC. This project is conducted in collaboration with Marcel Deckert and via multidisciplinary approaches combining omics and novel therapeutic approaches targeting SYK (new inhibitors and specific targeting of liver cells)