Kupke Paul, Yang Zhou Jordi, Glehr Gunther, Riquelme Paloma, Scheibert Lena, Adenugba Akinbami, Schlitt Hans J, Geissler Edward K, Werner Jens M, Hutchinson James A
Department of Surgery, University Hospital Regensburg, 93053, Regensburg, Germany.
Leibniz Institute for Immunotherapy, 93053, Regensburg, Germany.
Heliyon. 2024 Nov 30;10(23):e40841. doi: 10.1016/j.heliyon.2024.e40841. eCollection 2024 Dec 15.
Routine liver function tests capture information about the metabolic and inflammatory condition of the liver, but we lack sensitive biomarkers of early hepatocyte stress. In humans, soluble CD46 (sCD46) levels in blood were recently identified as an accurate biomarker of hepatic steatosis. Here, we explore the diagnostic utility of sCD46 in other liver diseases.
We developed, optimised and validated an ELISA that facilitates measurements of human sCD46 in plasma, serum and culture supernatants. Then, we analysed mechanisms that lead to the release of sCD46 and identified its role in various hepatic stress conditions.
We discovered that prostaglandin E2 (PGE2) drives upregulation of matrix metalloproteinase (MMP)-1 in fat-loaded hepatocytes, leading to proteolytic shedding of CD46. We further found that sCD46 release was increased by viral, toxic and hypoxic stresses.
sCD46 appears to be a promising biomarker with potential applications in the detection of early liver diseases or monitoring therapeutic responses, which could complement established diagnostic algorithms because sCD46 release is uniquely responsive to hepatocyte stress.
常规肝功能检查可获取有关肝脏代谢和炎症状况的信息，但我们缺乏早期肝细胞应激的敏感生物标志物。在人类中，血液中的可溶性CD46（sCD46）水平最近被确定为肝脂肪变性的准确生物标志物。在此，我们探讨sCD46在其他肝脏疾病中的诊断效用。
我们开发、优化并验证了一种酶联免疫吸附测定法（ELISA），该方法有助于测量血浆、血清和培养上清液中的人类sCD46。然后，我们分析了导致sCD46释放的机制，并确定了其在各种肝脏应激条件下的作用。
我们发现前列腺素E2（PGE2）促使脂肪负荷肝细胞中基质金属蛋白酶（MMP）-1上调，导致CD46的蛋白水解脱落。我们进一步发现，病毒、毒性和缺氧应激会增加sCD46的释放。
sCD46似乎是一种有前景的生物标志物，在早期肝脏疾病检测或监测治疗反应方面具有潜在应用，由于sCD46释放对肝细胞应激具有独特反应，它可以补充既定的诊断算法。
