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Abstract：
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic liver condition that often progresses to more advanced stages, such as metabolic dysfunction-associated steatohepatitis (MASH). MASH is characterized by inflammation and hepatocellular ballooning, in addition to hepatic steatosis. Despite the relatively high incidence of MASH in the population and its potential detrimental effects on human health, this liver disease is still not fully understood from a pathophysiological perspective. Deregulation of polyamine levels has been detected in various pathological conditions, including neurodegenerative diseases, inflammation, and cancer. However, the role of the polyamine pathway in chronic liver disorders such as MASLD has not been explored. In this study, we measured the expression of liver ornithine decarboxylase (ODC1), the rate-limiting enzyme responsible for the production of putrescine, and the hepatic levels of putrescine, in a preclinical model of MASH as well as in liver biopsies of patients with obesity undergoing bariatric surgery. Our findings reveal that expression of ODC1 and the levels of putrescine, but not spermidine nor spermine, are elevated in hepatic tissue of both diet-induced MASH mice and patients with biopsy-proven MASH compared with control mice and patients without MASH, respectively. Furthermore, we found that the levels of putrescine were positively associated with higher aspartate aminotransferase concentrations in serum and an increased SAF score (steatosis, activity, fibrosis). Additionally, in in vitro assays using human HepG2 cells, we demonstrate that elevated levels of putrescine exacerbate the cellular response to palmitic acid, leading to decreased cell viability and increased release of CK-18. Our results support an association between the expression of ODC1 and the progression of MASLD, which could have translational relevance in understanding the onset of this disease. © 2024 The Pathological Society of Great Britain and Ireland.
摘要：
代谢功能障碍相关的脂肪变性肝病（MASLD）是一种慢性肝病，通常进展到更晚期，如代谢功能障碍相关脂肪性肝炎（MASH）。MASH的特点是炎症和肝细胞膨胀，除了肝脂肪变性。尽管MASH在人群中的发病率相对较高，并且对人类健康有潜在的有害影响，从病理生理学的角度来看，这种肝脏疾病仍然没有完全理解。在各种病理条件下检测到多胺水平的失调，包括神经退行性疾病，炎症,和癌症。然而,多胺途径在慢性肝脏疾病如MASLD中的作用尚未被研究.在这项研究中,我们测量了肝脏鸟氨酸脱羧酶（ODC1）的表达，负责腐胺生产的限速酶，和腐胺的肝脏水平，在MASH的临床前模型以及接受减肥手术的肥胖患者的肝活检中。我们的发现揭示了ODC1的表达和腐胺的水平,但不是亚精胺也不是精胺，与对照小鼠和没有MASH的患者相比，饮食诱导的MASH小鼠和活检证实的MASH患者的肝组织均升高，分别。此外，我们发现，腐胺水平与血清中更高的天冬氨酸转氨酶浓度和SAF评分增加呈正相关（脂肪变性，活动,纤维化)。此外,在使用人HepG2细胞的体外测定中，我们证明腐胺水平升高会加剧细胞对棕榈酸的反应，导致细胞活力降低和CK-18释放增加。我们的结果支持ODC1的表达与MASLD进展之间的关联，这可能与理解这种疾病的发作具有翻译相关性。©2024英国和爱尔兰病理学会。
