Rao Prahlad K, Merath Kate, Drigalenko Eugene, Jadhav Avinash Y L, Komorowski Richard A, Goldblatt Matthew I, Rohatgi Anand, Sarzynski Mark A, Gawrieh Samer, Olivier Michael
1Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX USA.
2Biotechnology and Bioengineering Center, Medical College of Wisconsin, Milwaukee, WI USA.
Clin Proteomics. 2018 Mar 6;15:10. doi: 10.1186/s12014-018-9186-0. eCollection 2018.
Metabolic diseases such as obesity and diabetes are associated with changes in high-density lipoprotein (HDL) particles, including changes in particle size and protein composition, often resulting in abnormal function. Recent studies suggested that patients with non-alcoholic fatty liver disease (NAFLD), including individuals with non-alcoholic steatohepatitis (NASH), have smaller HDL particles when compared to individuals without liver pathologies. However, no studies have investigated potential changes in HDL particle protein composition in patients with NAFLD, in addition to changes related to obesity, to explore putative functional changes of HDL which may increase the risk of cardiovascular complications.
From a cohort of morbidly obese females who were diagnosed with simple steatosis (SS), NASH, or normal liver histology, we selected five matched individuals from each condition for a preliminary pilot HDL proteome analysis. HDL particles were enriched using size-exclusion chromatography, and the proteome of the resulting fraction was analyzed by liquid chromatography tandem mass spectrometry. Differences in the proteomes between the three conditions (normal, SS, NASH) were assessed using label-free quantitative analysis. Gene ontology term analysis was performed to assess the potential impact of proteomic changes on specific functions of HDL particles.
Of the 95 proteins identified, 12 proteins showed nominally significant differences between the three conditions. Gene ontology term analysis revealed that severity of the liver pathology may significantly impact the anti-thrombotic functions of HDL particles, as suggested by changes in the abundance of HDL-associated proteins such as antithrombin III and plasminogen.
The pilot data from this study suggest that changes in the HDL proteome may impact the functionality of HDL particles in NAFLD and NASH patients. These proteome changes may alter cardio-protective properties of HDL, potentially contributing to the increased cardiovascular disease risk in affected individuals. Further validation of these protein changes by orthogonal approaches is key to confirming the role of alterations in the HDL proteome in NAFLD and NASH. This will help elucidate the mechanistic effects of the altered HDL proteome on cardioprotective properties of HDL particles.
肥胖和糖尿病等代谢性疾病与高密度脂蛋白（HDL）颗粒的变化有关，包括颗粒大小和蛋白质组成的变化，常常导致功能异常。最近的研究表明，非酒精性脂肪性肝病（NAFLD）患者，包括非酒精性脂肪性肝炎（NASH）患者，与无肝脏病变的个体相比，其HDL颗粒较小。然而，尚无研究除了研究与肥胖相关的变化外，还调查NAFLD患者HDL颗粒蛋白质组成的潜在变化，以探索HDL可能增加心血管并发症风险的假定功能变化。
从一组被诊断为单纯性脂肪变性（SS）、NASH或肝脏组织学正常的病态肥胖女性队列中，我们从每种情况中选择了五名匹配个体进行初步的HDL蛋白质组分析。使用尺寸排阻色谱法富集HDL颗粒，并通过液相色谱串联质谱法分析所得馏分的蛋白质组。使用无标记定量分析评估三种情况（正常、SS、NASH）之间蛋白质组的差异。进行基因本体术语分析以评估蛋白质组变化对HDL颗粒特定功能的潜在影响。
在鉴定出的95种蛋白质中，有12种蛋白质在三种情况之间显示出名义上的显著差异。基因本体术语分析表明，肝脏病变的严重程度可能会显著影响HDL颗粒的抗血栓形成功能，抗凝血酶III和纤溶酶原等HDL相关蛋白丰度的变化表明了这一点。
本研究的初步数据表明，HDL蛋白质组的变化可能会影响NAFLD和NASH患者HDL颗粒的功能。这些蛋白质组变化可能会改变HDL的心脏保护特性，潜在地导致受影响个体心血管疾病风险增加。通过正交方法进一步验证这些蛋白质变化是确认HDL蛋白质组改变在NAFLD和NASH中的作用的关键。这将有助于阐明HDL蛋白质组改变对HDL颗粒心脏保护特性的机制性影响。
