Mocciaro Gabriele, George Amy L, Allison Michael, Frontini Mattia, Huang-Doran Isabel, Reiman Frank, Gribble Fiona, Griffin Julian L, Vidal-Puig Antonio, Azzu Vian, Kay Richard, Vacca Michele
Roger Williams Institute of Liver Studies, Foundation for Liver Research, London, UK.
Institute of Metabolic Science Metabolic Research Laboratories, Addenbrooke's Hospital, Cambridge, UK.
Liver Int. 2025 Feb;45(2):e16200. doi: 10.1111/liv.16200.
Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) encompasses a spectrum of histological conditions ranging from simple steatosis to fibrosing steatohepatitis, and is a risk factor for cardiovascular diseases (CVD). While oxidised apolipoproteins A and B have been linked to obesity and CVD, the association between other oxidised apolipoproteins and MASLD is yet to be established. To fill this gap, we characterised the circulating serum peptidome of patients with MASLD.
We studied the serum of 87 biopsy-confirmed MASLD patients and 20 age- and sex-matched control (CTRL) subjects. We first employed an untargeted LC-MS/MS peptidomics approach (9 CTRL, 32 MASLD) to identify key hits differentially modulated, and subsequently validated the most relevant findings through targeted peptidomics in an enlarged study population (87 MASLD and 20 CTRL).
Untargeted serum peptidomics identified several oxidised apolipoprotein peptide fragments, including ApoE and ApoC-III, significantly upregulated in MASLD compared to CTRL. Specifically focusing on the oxidative status of intact ApoC-III, studied through its major glycoforms (ApoC-III, ApoC-III and ApoC-III), we observed a marked reduction in non-oxidised forms of these circulating peptides alongside substantially increased levels of their oxidised proteoforms in MASLD versus controls (but not within the disease stages). Oxidised ApoE and ApoC-III peptide fragments were also significantly correlated with obesity, insulin resistance, dyslipidaemia and transaminases, suggesting a potential link between circulating apolipoprotein oxidation and systemic/hepatic metabolic dysfunction.
Our data reveals a previously unreported oxidised apolipoprotein profile associated with MASLD. The functional and clinical implications of these findings warrant further mechanistic investigation.
代谢功能障碍相关脂肪性肝病（MASLD）涵盖了从单纯性脂肪变性到纤维化性脂肪性肝炎的一系列组织学状况，并且是心血管疾病（CVD）的一个危险因素。虽然氧化型载脂蛋白A和B已与肥胖症及心血管疾病相关联，但其他氧化型载脂蛋白与MASLD之间的关联尚未确立。为填补这一空白，我们对MASLD患者的循环血清肽组进行了特征分析。
我们研究了87例经活检确诊的MASLD患者以及20名年龄和性别匹配的对照（CTRL）受试者的血清。我们首先采用非靶向液相色谱-串联质谱肽组学方法（9名CTRL，32名MASLD）来识别差异调节的关键靶点，随后在扩大的研究人群（87名MASLD和20名CTRL）中通过靶向肽组学对最相关的发现进行验证。
非靶向血清肽组学鉴定出了几个氧化型载脂蛋白肽片段，包括载脂蛋白E（ApoE）和载脂蛋白C-III（ApoC-III），与CTRL相比，在MASLD中显著上调。特别关注通过其主要糖型（ApoC-III1、ApoC-III2和ApoC-III3）研究的完整ApoC-III的氧化状态，我们观察到与对照组相比，这些循环肽的非氧化形式在MASLD中显著减少，同时其氧化蛋白形式的水平大幅增加（但在疾病阶段内没有这种情况）。氧化型ApoE和ApoC-III肽片段也与肥胖症、胰岛素抵抗、血脂异常和转氨酶显著相关，表明循环载脂蛋白氧化与全身/肝脏代谢功能障碍之间存在潜在联系。
我们的数据揭示了一种先前未报道的与MASLD相关的氧化型载脂蛋白谱。这些发现的功能和临床意义值得进一步进行机制研究。
