Castañé Helena, Jiménez-Franco Andrea, Hernández-Aguilera Anna, Martínez-Navidad Cristian, Cambra-Cortés Vicente, Onoiu Alina-Iuliana, Jiménez-Aguilar Juan Manuel, París Marta, Hernández Mercè, Parada David, Guilarte Carmen, Zorzano Antonio, Hernández-Alvarez María Isabel, Camps Jordi, Joven Jorge
Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, Universitat Rovira i Virgili, Institut d'Investigació Sanitària Pere Virgili, Reus, Spain; Department of Medicine and Surgery, Faculty of Medicine, Universitat Rovira i Virgili, Reus, Spain.
Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, Universitat Rovira i Virgili, Institut d'Investigació Sanitària Pere Virgili, Reus, Spain; Department of Medicine and Surgery, Faculty of Medicine, Universitat Rovira i Virgili, Reus, Spain.
EBioMedicine. 2025 Jan;111:105532. doi: 10.1016/j.ebiom.2024.105532. Epub 2024 Dec 27.
Metabolic dysfunction-associated steatotic liver disease (MASLD) and its more severe form steatohepatitis (MASH) contribute to rising morbidity and mortality rates. The storage of fat in humans is closely associated with these diseases' progression. Thus, adipose tissue metabolic homeostasis could be key in both the onset and progression of MASH.
We conducted a case-control observational research using a systems biology-based approach to analyse liver, abdominal subcutaneous adipose tissue (SAT), omental visceral adipose tissue (VAT), and blood of n = 100 patients undergoing bariatric surgery (NCT05554224). MASH was diagnosed through histologic assessment. Whole-slide image analysis, lipidomics, proteomics, and transcriptomics were performed on tissue samples. Lipidomics and proteomics profiles were determined on plasma samples.
Liver transcriptomics, proteomics, and lipidomics revealed interconnected pathways associated with inflammation, mitochondrial dysfunction, and lipotoxicity in MASH. Paired adipose tissue biopsies had larger adipocyte areas in both fat depots in MASH. Enrichment analyses of proteomics and lipidomics data confirmed the association of liver lesions with mitochondrial dysfunction in VAT. Plasma lipidomics identified candidates with high diagnostic accuracy (AUC = 0.919, 95% CI 0.840-0.979) for screening MASH.
Mitochondrial dysfunction is also present in VAT in patients with obesity-associated MASH. This may cause a disruption in the metabolic equilibrium of lipid processing and storage, which impacts the liver and accelerates detrimental adaptative responses.
The project leading to these results has received funding from 'la Caixa' Foundation (HR21-00430), and from the Instituto de Salud Carlos III (ISCIII) (PI21/00510) and co-funded by the European Union.
代谢功能障碍相关脂肪性肝病（MASLD）及其更严重的形式脂肪性肝炎（MASH）导致发病率和死亡率不断上升。人体脂肪储存与这些疾病的进展密切相关。因此，脂肪组织代谢稳态可能是MASH发病和进展的关键。
我们采用基于系统生物学的方法进行了一项病例对照观察性研究，分析了100例接受减肥手术患者（NCT05554224）的肝脏、腹部皮下脂肪组织（SAT）、网膜内脏脂肪组织（VAT）和血液。通过组织学评估诊断MASH。对组织样本进行全玻片图像分析、脂质组学、蛋白质组学和转录组学分析。对血浆样本进行脂质组学和蛋白质组学分析。
肝脏转录组学、蛋白质组学和脂质组学揭示了与MASH中炎症、线粒体功能障碍和脂毒性相关的相互关联的通路。配对的脂肪组织活检显示，MASH患者两个脂肪库中的脂肪细胞面积更大。蛋白质组学和脂质组学数据的富集分析证实了肝脏病变与VAT中线粒体功能障碍的关联。血浆脂质组学确定了用于筛查MASH诊断准确性高的候选物（AUC = 0.919，95% CI 0.840 - 0.979）。
肥胖相关MASH患者的VAT中也存在线粒体功能障碍。这可能导致脂质加工和储存的代谢平衡受到破坏，从而影响肝脏并加速有害的适应性反应。
导致这些结果的项目获得了“la Caixa”基金会（HR21 - 00430）、卡洛斯三世健康研究所（ISCIII）（PI21/00510）的资助，并由欧盟共同资助。
