目的:肥胖的增加凸显了对改进治疗策略的需求,特别是在解决代谢功能障碍相关的脂肪变性肝病(MASLD)。我们旨在评估色氨酸代谢途径在肥胖发病机理和MASLD不同组织学阶段中的作用。
方法:我们使用超高效液相色谱法定量来自犬尿氨酸的15种色氨酸相关代谢物的循环水平,吲哚和5-羟色胺途径。分析了76名受试者的队列,包括18名体重正常的受试者和58名病态肥胖的受试者,这些最后被分类为正常肝脏(NL),单纯性脂肪变性(SS)和代谢功能障碍相关脂肪性肝炎(MASH)。然后,我们进行了肝IDO-1和kynyrenine-3-单加氧酶(KMO)的基因表达分析。
结果:肥胖的主要发现揭示了一个独特的代谢特征,其特征是不同犬尿氨酸相关代谢物的浓度较高,吲哚-3-乙酸和吲哚-3-丙酸的减少,和血清素途径的改变。色氨酸水平升高与MASLD的存在有关(NL受试者中色氨酸为37.659(32.577-39.823)μM;MASLD患者为41.522(38.803-45.276)μM。总的来说,途径通量表明在SS受试者中通过5-羟色胺途径诱导色氨酸分解代谢,并在MASH中诱导进入犬尿氨酸途径。我们发现与SS相比,NL中IDO-1和KMO肝表达降低。
结论:我们在肥胖中发现了一个独特的代谢特征,其特征是色氨酸分解代谢途径的变化,通过改变的代谢物谱可辨别的。我们观察到MASLD中色氨酸分解代谢通量的阶段特异性变化,强调在治疗干预中靶向这些途径的潜在效用。
OBJECTIVE: The rise in obesity highlights the need for improved therapeutic strategies, particularly in addressing metabolic dysfunction-associated steatotic liver disease (MASLD). We aim to assess the role of tryptophan metabolic pathways in the pathogenesis of obesity and in the different histological stages of MASLD.
METHODS: We used ultra-high performance liquid chromatography to quantify circulating levels of 15 tryptophan-related metabolites from the kynurenine, indole and
serotonin pathways. A cohort of 76 subjects was analysed, comprising 18 subjects with normal weight and 58 with morbid obesity, these last being subclassified into normal liver (NL), simple steatosis (SS) and metabolic dysfunction-associated steatohepatitis (MASH). Then, we conducted gene expression analysis of hepatic IDO-1 and kynyrenine-3-monooxygenase (KMO).
RESULTS: Key findings in obesity revealed a distinct metabolic signature characterized by a higher concentration of different kynurenine-related metabolites, a decrease in indole-3-acetic acid and indole-3-propionic acid, and an alteration in the
serotonin pathway. Elevated tryptophan levels were associated with MASLD presence (37.659 (32.577-39.823) μM of tryptophan in NL subjects; 41.522 (38.803-45.276) μM in patients with MASLD). Overall, pathway fluxes demonstrated an induction of tryptophan catabolism via the
serotonin pathway in SS subjects and into the kynurenine pathway in MASH. We found decreased IDO-1 and KMO hepatic expression in NL compared to SS.
CONCLUSIONS: We identified a distinctive metabolic signature in obesity marked by changes in tryptophan catabolic pathways, discernible through altered metabolite profiles. We observed stage-specific alterations in tryptophan catabolism fluxes in MASLD, highlighting the potential utility of targeting these pathways in therapeutic interventions.