Longitudinal study of the development of Non-Alcoholic Fatty Liver disease (NAFLD). Key events and biomarker search
- Autores: María Martín Grau
- Directores de la Tesis: Daniel Monleon Salvado (dir. tes.), Vannina González Marrachelli (codir. tes.)
- Lectura: En la Universitat de València ( España ) en 2024
- Idioma: inglés
- Número de páginas: 432
- Títulos paralelos:
- Estudio longitudinal del desarrollo de la enfermedad del Hígado Graso No Alcohólico (NAFLF). Eventos clave y búsqueda de biomarcadores
- Tribunal Calificador de la Tesis: Antonio Vidal Puig (presid.), Consuelo Borrás Blasco (secret.), Antonio Pineda Lucena (voc.)
- Programa de doctorado: Programa de Doctorado en Medicina por la Universitat de València (Estudi General)
- Materias:
- Enlaces
- Tesis en acceso abierto en: RODERIC
- Resumen
Background & Aims: Nearly 30% of the world's population is affected by Non-alcoholic fatty liver disease (NAFLD). NAFLD is a liver disease which comprehends different stages, ranging from simple steatosis (NAFL) to hepatocellular carcinoma (HCC). NAFLD has different aetiologies, with several factors contributing to its development such as other metabolic diseases (obesity, T2DM, or metabolic syndrome), lifestyle, and genetics. Moreover, NAFLD prevalence is higher in males than in females, with sex hormones influencing in the liver metabolism. In addition, the microbiota has been considered a key player in the NAFLD as specific bacterial species have been directly associated with the development of the disease. Metabolomics has become a powerful tool for studying the molecular signatures and metabolic dysregulations of different metabolic diseases, including NAFLD. The aim of this research was to investigate metabolic changes during NAFLD progression, for identifying the sequence of events and evaluating the impact of sexual dimorphism and the microbiome on the initial stages of NAFLD development.
Methods: Male and female Wistar rats were randomly divided into different groups, fed with a chow diet (CTL group) or a 45% high-fat diet (HFD group) for 21 weeks. Every three weeks, samples of serum, urine, and faeces were collected to perform the longitudinal analysis. After 21 weeks, the animals were sacrificed. The tissues were stained to perform a histopathological assessment. Serum, urine, faeces, and liver samples were studied by nuclear magnetic resonance (NMR) spectrometer. In addition, the gut microbiota was analysed by qPCR.
Results: The liver histopathological analysis revealed an early steatosis. In the liver metabolome, the main differences were related to the lipid moieties. However, significant metabolites were only observed in the liver of HFD males, suggesting that the disease had a more severe pattern in males than in females. In the serum metabolome, specific lipid subtypes and specific altered metabolites from week 9 were found in males and females. Nonetheless, the samples where the most metabolomic differences were found were urine and faeces, which of some appeared from week 3. In addition, metabolites related to the host-microbiota co-metabolism were found in all the samples. Finally, the microbiota analysis revealed changes in microbiota diversity.
Conclusion: Metabolomics allowed the identification of specific metabolic signatures in serum, urine, faeces, and liver, proposing valuable biomarkers in the early development of NAFLD. The longitudinal study allowed us to establish the sequence of events in the early development of NAFLD elucidating sexual dimorphism and the microbiota role. Our study suggested that changes in gut microbiota precede changes in the host metabolism in the early stages of NAFLD. Moreover, males experienced greater changes in the general metabolism than females
