Study of pharmacological treatments in high fat diet mouse models in order to identify novel therapeutic targets for metabolic dysfunctionassociated steatotic liver disease
- Autores: Isabel Fuster Martínez
- Directores de la Tesis: Juan V. Esplugues Mota (dir. tes.), Nadezda Apostolova (codir. tes.), Ana Blas García (codir. tes.)
- Lectura: En la Universitat de València ( España ) en 2024
- Idioma: inglés
- Número de páginas: 266
- Tribunal Calificador de la Tesis: Marta María Varela Rey (presid.), Douglas Maya Miles (secret.), Vanessa Pellegrinelli (voc.)
- Programa de doctorado: Programa de Doctorado en Biomedicina y Farmacia por la Universitat de València (Estudi General)
- Materias:
- Enlaces
- Tesis en acceso abierto en: webges.uv.es (pdf)
- Resumen
Metabolic dysfunction-associated steatotic liver disease (MASLD), the most prevalent chronic liver disease, consists of altered lipid accumulation in the liver that triggers hepatotoxicity. Although it is initially a benign condition, it can progress to steatohepatitis, fibrosis and eventually, cirrhosis. Due to the lack of effective pharmacological therapies for MASLD in the clinics, intensive preclinical research is being conducted, in which high fat diet (HFD) mouse models of MASLD are crucial.
In this PhD project, we aimed to investigate the mechanisms underlying the effects of several pharmacological treatments in HFD murine models in order to search for new therapeutic targets.
Firstly, we characterized the common transcriptomic signature of different HFD mouse models and its modulation by anti-steatotic treatments through a meta-analysis of transcriptomic data sets from the literature. Among the genes with potential interest, we further investigated PPIC, whose expression was also increased in other mouse and cellular models of hepatic injury. Interestingly, in a hepatocyte cell line, silencing PPIC downregulated some pro-inflammatory factors, while, in a hepatic stellate cell line, it triggered several cellular stress response pathways along with a pro-fibrotic effect. Altogether, these results pointed to pleiotropic functions of PPIC in the liver.
Furthermore, we delved into the mechanisms behind the hepatoprotective properties of one of the drugs included in the meta-analysis, rilpivirine (RPV). For that reason, we examined its impact on the hepatic lipidome and the adipose tissue (AT) in a HFD mouse model. Our results revealed that RPV counteracted the effects of the HFD on several parameters such as the hepatic content of triglycerides and ether-linked phospholipids, and the expression of adipogenic markers, fibrotic markers and endocrine mediators in inguinal AT. Additionally, we studied the effect of RPV on hepatoma cells under a lipotoxic stimulus, observing that RPV downregulated the inflammatory response.
We also investigated the impact of inhibiting FDFT1, an enzyme involved in the cholesterol biosynthesis, on hepatoxicity and AT. The data obtained suggested that the substrate of FDFT1, farnesyl pyrophosphate, acted as a paracrine signal for cell death and a pro-adipogenic factor.
In conclusion, this thesis provides a comprehensive study of the effect of different anti-steatotic treatments on the liver transcriptome, which may help to drive new hypotheses for the identification of potential biomarkers and therapeutic targets for MASLD. It also contributes to the understanding of the impact of the antiretroviral drug RPV on the liver and the AT, reinforcing its therapeutic value against MASLD. Finally, it offers interesting data regarding the effect of modulating cholesterol biosynthetic pathway in the context of MASLD, showing FPP as an active metabolite both in the liver and the AT.
