α -氨基丁酸通过增强AMPK/SIRT1通路和调节肠-肝轴改善小鼠饮食诱导的代谢功能障碍相关脂肪变性肝病（MASLD）进展

IF 4.8 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Nutritional Biochemistry Pub Date : 2025-02-25 DOI:10.1016/j.jnutbio.2025.109885

Felicianna , Emily Kwun Kwan Lo , Congjia Chen , Marsena Jasiel Ismaiah , Fangfei Zhang , Hoi Kit Matthew Leung , Hani El-Nezami

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引用次数: 0

摘要

α -氨基丁酸（ABA）是一种非蛋白质源性氨基酸，可由蛋氨酸、苏氨酸、丝氨酸和甘氨酸代谢产生，也可作为肠道微生物衍生的代谢物。ABA水平的变化已被卷入代谢功能障碍相关脂肪变性肝病（MASLD）干预研究中，但其与MASLD发病机制的关系尚不清楚。因此，本研究旨在探讨口服ABA补充对高脂肪/高胆固醇饮食（HFD）诱导的MASLD小鼠模型进展的影响。研究发现，ABA可以改变hfd喂养小鼠的肠道微生物组成，改善MASLD参数。ABA减轻了hfd引起的肝脏重量增加、肝脂肪变性、胰岛素抵抗、血清和肝脏甘油三酯水平以及肝脏胆固醇水平。在肝脏中观察到脂质代谢的调节，其中参与新生脂肪生成的蛋白质和/或基因的表达被抑制，而参与脂肪酸氧化和自噬的蛋白质和/或基因的表达上调，以及细胞抗氧化能力，以及AMPK/SIRT1途径的增强。ABA通过增加9种细菌（包括Helicobacter hepatitis， Desulfovibrio sp. G11， parabobacterides disasonis和Bacteroides fragilis）来重塑肠道组成，同时减少16种细菌的丰度，其中包括4种幽门螺杆菌。微生物功能的KEGG通路分析发现，ABA阻碍了次生胆汁酸的生物合成——这在粪便BA组成分析中得到了反映。值得注意的是，ABA还抑制回肠FXR-Fgf15信号传导，允许增加肝脏Cyp7a1表达，以消除肝脏中的胆固醇积聚。总之，我们的研究结果表明，ABA可以作为一种有希望的治疗方法来干预MASLD。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Alpha-aminobutyric acid ameliorates diet-induced metabolic dysfunction-associated steatotic liver disease (MASLD) progression in mice via enhancing AMPK/SIRT1 pathway and modulating the gut-liver axis

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Alpha-aminobutyric acid (ABA) is a nonproteinogenic amino acid, a metabolite which could be generated from the metabolism of methionine, threonine, serine and glycine or as a gut-microbiome-derived metabolite. Changes in ABA levels have been embroiled in metabolic dysfunction-associated steatotic liver disease (MASLD) intervention studies, but their relation to MASLD pathogenesis remains unclear. Hence, this present study aimed to investigate the effect of oral ABA supplementation on the progression of a high fat/high cholesterol diet (HFD) induced MASLD mice model. ABA was found to remodel the gut microbiome composition and ameliorate MASLD parameters in HFD-fed mice. ABA mitigated HFD-induced gain in liver weight, hepatic steatosis, insulin resistance, serum and hepatic triglyceride levels, and liver cholesterol levels. Modulation of lipid metabolism was observed in the liver, in which expression of proteins and/or genes involved in de novo lipogenesis were suppressed, while those involved in fatty acid oxidation and autophagy were upregulated together with cellular antioxidant capacity, in addition to the enhancement of the AMPK/SIRT1 pathway. ABA reshaped the gut composition by enriching nine bacterial species, including Helicobacter hepaticus, Desulfovibrio sp. G11, Parabacteroides distasonis, and Bacteroides fragilis, while diminishing the abundance of 16 species, which included four Helicobacter species. KEGG pathway analysis of microbial functions found that ABA impeded secondary bile acid biosynthesis – which was reflected in the faecal BA composition analysis. Notably, ABA also inhibited ileal FXR-Fgf15 signaling, allowing for increased hepatic Cyp7a1 expression to eliminate cholesterol buildup in the liver. Overall, our findings indicate that ABA could be used as a promising therapeutic approach for the intervention of MASLD.

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来源期刊

Journal of Nutritional Biochemistry 医学-生化与分子生物学

CiteScore

9.50

自引率

3.60%

发文量

237

审稿时长

68 days

期刊介绍： Devoted to advancements in nutritional sciences, The Journal of Nutritional Biochemistry presents experimental nutrition research as it relates to: biochemistry, molecular biology, toxicology, or physiology. Rigorous reviews by an international editorial board of distinguished scientists ensure publication of the most current and key research being conducted in nutrition at the cellular, animal and human level. In addition to its monthly features of critical reviews and research articles, The Journal of Nutritional Biochemistry also periodically publishes emerging issues, experimental methods, and other types of articles.