Unravelling the contribution of adipose tissue macrophages to metabolic dysfunction-associated steatotic liver disease
[eng] Nonalcoholic fatty liver disease (GHD) is a very prevalent liver condition, especially linked to obesity and type 2 diabetes. It affects about 30% of the world's population and can evolve into more serious forms such as metabolic steatohepatitis (MASH) and liver cirrhosis. EGHNA is ch...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2025 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/223480 |
| Acceso en línea: | https://hdl.handle.net/2445/223480 http://hdl.handle.net/10803/695373 |
| Access Level: | acceso abierto |
| Palabra clave: | Malalties del fetge Teixit adipós Macròfags Liver diseases Adipose tissues Macrophages |
| Sumario: | [eng] Nonalcoholic fatty liver disease (GHD) is a very prevalent liver condition, especially linked to obesity and type 2 diabetes. It affects about 30% of the world's population and can evolve into more serious forms such as metabolic steatohepatitis (MASH) and liver cirrhosis. EGHNA is characterized by excessive fat accumulation in the liver and an exacerbated inflammatory response. In addition to the liver, adipose tissue plays a key role, as the accumulation of visceral fat and its metabolic dysfunction contribute to the progression of the disease. In obesity, adipose tissue is hypertrophied and causes chronic inflammation with an increase in adipose tissue macrophages (TMJs). These macrophages have been linked to insulin resistance and liver inflammation, but their role in the advanced stages of the disease is not fully understood. This thesis hypothesizes that TMJs adapt their phenotype and functionality in response to liver damage and systemic inflammation. For this reason, the following have been studied: The accumulation and phenotype of TMJs throughout the EGHNA and their contribution to liver damage in the fibrosis phase, using human samples and mouse models. The therapeutic potential of TMJs, modulating their inflammatory-active phenotype by dextran conjugates with dexamethasone (DD) in mouse models. The identification of a key subpopulation of macrophages, through sequencing, to understand their role in disease progression. The results have shown that proinflammatory TMJs increase in patients with advanced EHGM, contributing to liver fibrosis. Modulation of TMJs in mouse models with DD reduced inflammation in both adipose tissue and liver, improving markers of liver damage. In addition, a subpopulation of perivascular macrophages was identified that increases in advanced stages and could play a role in dysfunctional angiogenesis. The hypoxic environment seems to favour this phenotype, and its reduction has been associated with an improvement in the disease. In conclusion, the thesis demonstrates a direct association between adipose tissue macrophages and the progression of liver fibrosis, proposing them as a potential therapeutic target to slow down the progression of EGNA. It also identifies a specific type of perivascular macrophages that could contribute to angiogenesis and aggravate the disease. |
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