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Abstract：
Globally, metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed nonalcoholic fatty liver disease (NAFLD), is one of the most common liver disorders and is strongly associated with copper deficiency. To explore the potential effects and mechanisms of Lactiplantibacillus plantarum LPJZ-658, copper deficiency combined with a high-sugar diet-induced MASLD mouse model was utilized in this study. We fed 40-week-old (middle-aged) male C57BL/6 mice a copper-deficient and high-sugar diet for 16 weeks (CuDS), with supplementary LPJZ-658 for the last 6 weeks (CuDS + LPJZ-658). In this study, we measured body weight, liver weight, and serum biochemical markers. Lipid accumulation, histology, lipidomics, and sphingolipid metabolism-related enzyme expression were investigated to analyze liver function. Untargeted metabolomics was used to analyze the serum and the composition and abundance of intestinal flora. In addition, the correlation between differential liver lipid profiles, serum metabolites, and gut flora at the genus level was measured. The results show that LPJZ-658 significantly improves abnormal liver function and hepatic steatosis. The lipidomics analyses and metabolic pathway analysis identified sphingolipid, retinol, and glycerophospholipid metabolism as the most relevant metabolic pathways that characterized liver lipid dysregulation in the CuDS group. Consistently, RT-qPCR analyses revealed that the enzymes catalyzing sphingolipid metabolism that were significantly upregulated in the CuDS group were downregulated by the LPJZ-658 treatment. In addition, the serum metabolomics results indicated that the linoleic acid, taurine and hypotaurine, and ascorbate and aldarate metabolism pathways were associated with CuDS-induced MASLD. Notably, we found that treatment with LPJZ-658 partially reversed the changes in the differential serum metabolites. Finally, LPJZ-658 effectively regulated intestinal flora abnormalities and was significantly correlated with differential hepatic lipid species and serum metabolites. In conclusion, we elucidated the function and potential mechanisms of LPJZ-658 in alleviating copper deficiency combined with sugar-induced middle-aged MASLD and hope this will provide possible treatment strategies for improving MASLD.
摘要：
全球范围内,代谢功能障碍相关的脂肪变性肝病（MASLD），以前称为非酒精性脂肪性肝病（NAFLD），是最常见的肝脏疾病之一，与铜缺乏密切相关。为了探索植物乳杆菌LPJZ-658的潜在作用和机制，本研究利用了铜缺乏联合高糖饮食诱导的MASLD小鼠模型。我们给40周龄（中年）雄性C57BL/6小鼠喂食缺铜和高糖饮食16周（CuDS），最后6周补充LPJZ-658（CuDS+LPJZ-658）。在这项研究中,我们测量了体重，肝脏重量,和血清生化标志物。脂质积累，组织学,脂质组学，和鞘脂代谢相关酶的表达进行肝功能分析。非靶向代谢组学用于分析血清和肠道菌群的组成和丰度。此外,不同肝脂质分布之间的相关性，血清代谢物，并测量了属水平的肠道菌群。结果显示,LPJZ-658显著改善异常肝功能和肝性脂肪变性。脂质组学分析和代谢途径分析确定了鞘脂，视黄醇,和甘油磷脂代谢是CuDS组中表征肝脏脂质失调的最相关的代谢途径。始终如一，RT-qPCR分析揭示在CuDS组中显著上调的催化鞘脂代谢的酶被LPJZ-658处理下调。此外,血清代谢组学结果表明,亚油酸,牛磺酸和次牛磺酸,抗坏血酸和醛盐代谢途径与CuDS诱导的MASLD相关。值得注意的是,我们发现,LPJZ-658治疗部分逆转了差异血清代谢物的变化.最后,LPJZ-658可有效调节肠道菌群异常，并与差异肝脂质种类和血清代谢产物显着相关。总之,我们阐明了LPJZ-658在缓解缺铜联合糖诱导的中年MASLD方面的功能和潜在机制,并希望这将为改善MASLD提供可能的治疗策略.
