Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, Kentucky; Department of Pharmacology and Toxicology, University of Louisville Alcohol Center, Louisville, Kentucky.
Biological Sciences Division and Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, Washington.
Am J Pathol. 2022 Jul;192(7):1066-1082. doi: 10.1016/j.ajpath.2022.04.004. Epub 2022 Apr 28.
Alcohol-associated liver disease is a global health care burden, with alcohol-associated cirrhosis (AC) and alcohol-associated hepatitis (AH) being two clinical manifestations with poor prognosis. The limited efficacy of standard of care for AC and AH highlights a need for therapeutic targets and strategies. The current study aimed to address this need through the identification of hepatic proteome and phosphoproteome signatures of AC and AH. Proteomic and phosphoproteomic analyses were conducted on explant liver tissue (test cohort) and liver biopsies (validation cohort) from patients with AH. Changes in protein expression across AH severity and similarities and differences in AH and AC hepatic proteome were analyzed. Significant alterations in multiple proteins involved in various biological processes were observed in both AC and AH, including elevated expression of transcription factors involved in fibrogenesis (eg, Yes1-associated transcriptional regulator). Another finding was elevated levels of hepatic albumin (ALBU) concomitant with diminished ALBU phosphorylation, which may prevent ALBU release, leading to hypoalbuminemia. Furthermore, altered expression of proteins related to neutrophil function and chemotaxis, including elevated myeloperoxidase, cathelicidin antimicrobial peptide, complement C3, and complement C5 were observed in early AH, which declined at later stages. Finally, a loss in expression of mitochondria proteins, including enzymes responsible for the synthesis of cardiolipin was observed. The current study identified hepatic protein signatures of AC and AH as well as AH severity, which may facilitate the development of therapeutic strategies.
酒精相关性肝病是全球医疗保健的负担，其中酒精相关性肝硬化（AC）和酒精相关性肝炎（AH）是两种临床表现，预后不良。AC 和 AH 的标准治疗效果有限，这凸显了对治疗靶点和策略的需求。本研究旨在通过鉴定 AC 和 AH 的肝蛋白质组和磷酸蛋白质组特征来满足这一需求。对来自 AH 患者的肝组织（测试队列）和肝活检（验证队列）进行了蛋白质组学和磷酸蛋白质组学分析。分析了 AH 严重程度中蛋白质表达的变化，以及 AH 和 AC 肝蛋白质组之间的相似性和差异。在 AC 和 AH 中均观察到多种参与各种生物学过程的蛋白质表达发生显著改变，包括参与纤维化的转录因子（如 Yes1 相关转录调节剂）的表达上调。另一个发现是肝白蛋白（ALBU）水平升高，同时 ALBU 磷酸化减少，这可能阻止 ALBU 释放，导致低白蛋白血症。此外，在早期 AH 中观察到与中性粒细胞功能和趋化有关的蛋白质表达改变，包括髓过氧化物酶、抗菌肽 cathelicidin、补体 C3 和补体 C5 升高，而在后期阶段这些蛋白表达下降。最后，观察到线粒体蛋白表达的丧失，包括负责心磷脂合成的酶。本研究确定了 AC 和 AH 以及 AH 严重程度的肝蛋白质组特征，这可能有助于开发治疗策略。
