Lo Emily Kwun Kwan, Chen Congjia, Ismaiah Marsena Jasiel, Zhang Fangfei, Leung Hoi Kit Matthew, El-Nezami Hani
School of Biological Sciences, University of Hong Kong, Pokfulam, Hong Kong, China.
School of Biological Sciences, University of Hong Kong, Pokfulam, Hong Kong, China; Institute of Public Health and Clinical Nutrition, School of Medicine, University of Eastern Finland, Kuopio, Finland.
J Nutr Biochem. 2025 Jun;140:109885. doi: 10.1016/j.jnutbio.2025.109885. Epub 2025 Feb 25.
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.
α-氨基丁酸（ABA）是一种非蛋白质氨基酸，是一种可由甲硫氨酸、苏氨酸、丝氨酸和甘氨酸代谢产生的代谢物，或作为肠道微生物群衍生的代谢物。ABA水平的变化已涉及代谢功能障碍相关脂肪性肝病（MASLD）的干预研究，但其与MASLD发病机制的关系仍不清楚。因此，本研究旨在探讨口服补充ABA对高脂/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可重塑肠道微生物群组成，并改善HFD喂养小鼠的MASLD参数。ABA减轻了HFD诱导的肝脏重量增加、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，其中参与从头脂肪生成的蛋白质和/或基因的表达受到抑制，而参与脂肪酸氧化和自噬的蛋白质和/或基因与细胞抗氧化能力一起上调，同时增强了AMPK/SIRT1通路。ABA通过富集9种细菌物种重塑肠道组成，包括肝螺杆菌、脱硫弧菌属G11、多形拟杆菌和脆弱拟杆菌，同时减少了16种细菌的丰度，其中包括4种螺杆菌属。对微生物功能的KEGG通路分析发现，ABA阻碍了次级胆汁酸的生物合成——这在粪便胆汁酸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，从而增加肝脏Cyp7a1表达以消除肝脏中的胆固醇积累。总体而言，我们的研究结果表明，ABA有望作为干预MASLD的治疗方法。
