RT info:eu-repo/semantics/doctoralThesis
T1 Estudio del papel de lipina-2 en la regulación de la homeostasis del colesterol en macrófagos: implicaciones en la respuesta a lipoproteínas aterogénicas
A1 Martínez García, Javier
A2 Universidad de Valladolid. Escuela de Doctorado
K1 Colesterol
K1 Macrophage
K1 Macrófago
K1 Atherosclerosis
K1 Aterosclerosis
K1 Cholesterol
K1 Colesterol
K1 Inflammation
K1 Inflamación
K1 3109.03 Inmunología
AB This thesis delves into the role of lipin-2 as a key regulator of cholesterol homeostasis, inflammatory response, and energy metabolism in macrophages, particularly under stimulation with oxidized lipoproteins (OxLDL). In the context of inflammatory diseases such as atherosclerosis, macrophages play a central role in both lipid uptake and immune responses, making it essential to understand the molecular mechanisms that govern these processes.One of the main findings of this work is that lipin-2 deficiency impairs the ability of macrophages to maintain intracellular cholesterol levels in the absence of an exogenous source. This impairment is linked to defective activation of the AKT/mTOR pathway, which prevents nuclear translocation of the transcription factor SREBP-2, essential for the expression of genes involved in de novo cholesterol synthesis. Interestingly, this defect is reversed by the simultaneous deletion of lipin-1, suggesting an antagonistic regulatory effect between these isoforms in SREBP-2 activation.Moreover, lipin-2 deficiency does not affect LDL receptor expression or its membrane localization and uptake, but it does lead to reduced cholesterol synthesis and increased efflux capacity mediated by the transporters ABCA1 and ABCG1. This may account for the overall reduction in cellular cholesterol content observed in these cells.Under inflammatory conditions, such as OxLDL exposure, lipin-2–deficient macrophages exhibit an exacerbated response characterized by elevated production of cytokines and inflammatory mediators, as well as enhanced activation of the inflammasome. This response is further amplified by increased expression of the scavenger receptor CD36, whose signaling, in cooperation with TLR4, constitutes a central axis driving the observed inflammation and metabolic dysfunction.At the mitochondrial level, OxLDL stimulation in the absence of lipin-2 promotes a metabolic shift toward glycolysis, accompanied by decreased electron transport chain activity and increased mitochondrial ROS production. These effects are associated with downregulation of antioxidant genes and can be reversed by overexpression of mitochondrial catalase (mCAT), highlighting a key role of oxidative stress in the alterations triggered by lipin-2 deficiency.Additionally, disturbances in lipid metabolism are evident, including the accumulation of diacylglycerols (DAG), reduction in triacylglycerols (TAG) and cholesterol esters (CE), and decreased lipid droplet formation. These changes may be linked to impaired mobilization of intracellular cholesterol and lysosomal dysfunction in lipin-2–deficient macrophages.Altogether, this study demonstrates that lipin-2 functions as an integrative node linking cholesterol metabolism, mitochondrial function, and immune response in macrophages. Its deficiency not only disrupts lipid homeostasis but also enhances OxLDL-induced inflammation, potentially contributing to the progression of chronic inflammatory diseases such as atherosclerosis. These findings not only deepen our understanding of lipin function in immunometabolism but also open new avenues for exploring therapeutic strategies aimed at modulating lipin-2 activity in cardiovascular disease.
YR 2024
FD 2024
LK https://uvadoc.uva.es/handle/10324/80038
UL https://uvadoc.uva.es/handle/10324/80038
LA spa
NO Escuela de Doctorado
DS UVaDOC
RD 24-nov-2025