RESUMEN
Abdominal aortic aneurysm (AAA) is an insidious and lethal vascular disease that lacks effective nonsurgical interventions. Gut microbiota dysbiosis plays key roles in many diseases, but its relationship with AAA has not been fully elucidated. Herein, we reveal significant abnormalities in the gut microbe composition of AAA patients and confirm that gut microbiota dysbiosis is an important cause of AAA. Specifically, R. intestinalis was significantly reduced in AAA patients. Using AAA mice, we show that R. intestinalis and its metabolite butyrate significantly reduce neutrophil infiltration and NOX2-dependent neutrophil extracellular trap formation, inflammation, and abnormal phenotypic switching of vascular smooth muscle cells in the aortic wall, thereby markedly alleviating AAA development. Our research uncovers the role and mechanism of the gut microbiota in AAA development and provides insights into AAA prophylaxis from a microecological perspective.
Asunto(s)
Aneurisma de la Aorta Abdominal , Trampas Extracelulares , Microbioma Gastrointestinal , Animales , Aorta Abdominal/metabolismo , Aneurisma de la Aorta Abdominal/metabolismo , Aneurisma de la Aorta Abdominal/prevención & control , Butiratos/metabolismo , Modelos Animales de Enfermedad , Disbiosis/metabolismo , Trampas Extracelulares/metabolismo , Ratones , Ratones Endogámicos C57BLRESUMEN
The elevated thyroid-stimulating hormone (TSH) levels contribute to the abnormal expression/activity of several key hepatic lipid metabolism enzymes. Although miRNAs have been shown to play key roles in hepatic lipid metabolism and are found in isolated mitochondria, very little is known about the pathological and physiological significance of their mitochondrial distributions in regulating liver lipid metabolism. Here, we found that TSH significantly reduced the distribution of some miRNAs in mitochondria of hepatocytes, especially miR-449a, miR-449b-5p, and miR-5194. These three miRNAs inhibited their target genes PGC1B, ABCD1, ADIPOR1 and the downstream molecule PPARA. These effects synergistically suppressed fatty acid (FA) ß-oxidation in mitochondria and peroxisomes and decreased the translocation of cytosolic very long chain fatty acids to peroxisomes, which noticeably reduced FA catabolism and promoted triglyceride accumulation in hepatocytes. This study reveals the functional significance of changed miRNA mitochondrial-cytoplasmic distribution in the regulation of hepatic lipid metabolism.