代谢功能障碍相关的脂肪变性肝病(MASLD)是一种慢性,包括一系列脂肪变性的进行性肝病,脂肪性肝炎(或MASH),和纤维化。有证据表明,饮食限制(DR)和袖状胃切除术(SG)可以通过体重减轻来缓解肝脏脂肪变性和炎症,但目前尚不清楚这些方法是否会在MASLD肝脏中引起明显的代谢或免疫变化。本研究旨在阐明DR后复杂的肝脏变化,高脂饮食大鼠的SG或假手术作为肥胖相关MASLD的模型,与接受SG的患者的临床队列相比。单细胞和单核转录组分析,空间代谢组学,免疫组织化学揭示了肝脏的景观,同时在血清样本中测量循环生物标志物。人工智能(AI)辅助图像分析表征肝细胞的空间分布,骨髓细胞和淋巴细胞。在患者和实验性MASLD大鼠中,SG改善体重指数,循环肝损伤生物标志物和甘油三酯水平。DR和SG均减轻大鼠肝脏脂肪变性和纤维化。代谢相关基因(PPara,Cyp2e1和Cyp7a1)在DR和SG后的肝细胞中上调,而SG广泛上调胆管细胞的脂质代谢,单核细胞,巨噬细胞,和中性粒细胞。此外,SG促进肝脏中恢复性骨髓细胞的积累,不仅改善炎症,而且激活肝脏修复过程。SG后,具有有效髓样浸润的区域具有增强的代谢能力。此外,在DR上观察到门静脉周围肝细胞功能的破坏。总之,这项研究表明,接受SG的患者的脂肪变性肝脏中存在动态细胞串扰。值得注意的是,PPARα和肠-肝轴相关过程,和代谢活跃的骨髓细胞浸润表明干预相关机制支持SG治疗MASLD的适应症。
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic, progressive liver disease that encompasses a spectrum of steatosis, steatohepatitis (or MASH), and fibrosis. Evidence suggests that dietary restriction (DR) and sleeve gastrectomy (SG) can lead to remission of hepatic steatosis and inflammation through weight loss, but it is unclear whether these procedures induce distinct metabolic or immunological changes in MASLD livers. This study aims to elucidate the intricate hepatic changes following DR, SG or sham surgery in rats fed a high-fat diet as a model of obesity-related MASLD, in comparison to a clinical cohort of patients undergoing SG. Single-cell and single-nuclei transcriptome analysis, spatial metabolomics, and immunohistochemistry revealed the liver landscape, while circulating biomarkers were measured in serum samples. Artificial intelligence (AI)-assisted image analysis characterized the spatial distribution of hepatocytes, myeloid cells and lymphocytes. In patients and experimental MASLD rats, SG improved body mass index, circulating liver injury biomarkers and triglyceride levels. Both DR and SG attenuated liver steatosis and fibrosis in rats. Metabolism-related genes (Ppara, Cyp2e1 and Cyp7a1) were upregulated in hepatocytes upon DR and SG, while SG broadly upregulated lipid metabolism on cholangiocytes, monocytes, macrophages, and neutrophils. Furthermore, SG promoted restorative myeloid cell accumulation in the liver not only ameliorating inflammation but activating liver repair processes. Regions with potent myeloid infiltration were marked with enhanced metabolic capacities upon SG. Additionally, a disruption of periportal hepatocyte functions was observed upon DR. In conclusion, this study indicates a dynamic cellular crosstalk in steatotic livers of patients undergoing SG. Notably, PPARα- and gut-liver axis-related processes, and metabolically active myeloid cell infiltration indicate intervention-related mechanisms supporting the indication of SG for the treatment of MASLD.