HSPG Interactions in Liver Disease

摘要 R 01提案的中心目标是了解乙酰肝素的分子和细胞相互作用 硫酸蛋白多糖（HSPGs）调节对乙酰氨基酚（APAP）诱导的肝损伤的发病机制 （AILI）. APAP的意外或故意滥用是西方世界急性肝衰竭的主要原因。 虽然触发AILI的机制是众所周知的，但那些促进肝脏恢复的机制却鲜为人知。 HSPG通过其硫酸乙酰肝素（HS）链结合并调节各种组织损伤因子，但HSPG的作用机制与其自身的作用机制不同。 HSPG在体内组织损伤和修复中的意义和机制仍然很不清楚。我们 研究了syndecan-1（Sdc 1），肝细胞的主要细胞表面HSPG，在AILI中的作用。删除Sdc 1 导致APAP肝病中肝损伤的无对抗进展。然而，直接APAP肝毒性 在APAP过量后的早期，Sdc 1缺失不受影响，这表明Sdc 1调节后， 影响APAP肝病进展和结局的机制。旺盛的AILI表型 Sdc 1 null（Sdc 1-/-）小鼠被追踪到肝脏中夸大的先天免疫应答和 在肝细胞中促存活Akt信号传导和肝细胞增殖中，这导致肝细胞扩增， 损害施用纯化的Sdc 1或含有2-O-硫酸基序的类肝素化合物拯救了Sdc 1-/- 通过抑制先天性免疫应答，并通过增强肝细胞增殖和肝脏 修复.此外，与N-乙酰半胱氨酸相比，HS显示出显著延长的治疗功效 (NAC)APAP过量的临床解毒剂。这些发现表明，Sdc 1和HS，无论是单独或在 联合NAC，可以提供一种新的治疗策略，以对抗AILI，特别是在治疗患者 接受NAC治疗后不再有效。基于这些初步数据，我们提出Sdc 1是 一种关键的内源性因子，可阻止AILI中肝损伤的持续并促进肝修复。这 假设将在3个具体目标中进行测试。目的1将定义Sdc 1如何从肝细胞中释放， AILI和建立的离散结构基序在Sdc 1 HS提供保护，防止AILI。目标2将 阐明Sdc 1如何阻止AILI进展的生物学机制。目标3将决定Sdc 1如何 增强肝细胞增殖并促进AILI中的肝修复。预计这些研究将建立一个 肝损伤和修复的新整合途径。

ABSTRACT The central goal of this R01 proposal is to understand how molecular and cellular interactions of heparan sulfate proteoglycans (HSPGs) modulate the pathogenesis of acetaminophen (APAP)-induced liver injury (AILI). Accidental or intentional misuse of APAP is the leading cause of acute liver failure in the Western world. While mechanisms that trigger AILI are well known, those that facilitate liver recovery are less understood. HSPGs bind and regulate various tissue injury factors through their heparan sulfate (HS) chains, but the significance and mechanisms of HSPGs in tissue injury and repair in vivo remain largely unknown. We examined the role of syndecan-1 (Sdc1), the major cell surface HSPG of hepatocytes, in AILI. Deletion of Sdc1 in mice led to unopposed progression of liver injury in APAP liver disease. However, direct APAP hepatoxicity at early times after APAP overdose was unaffected by Sdc1 deletion, suggesting that Sdc1 regulates later mechanisms that affect the progression and outcome of APAP liver disease. The exuberant AILI phenotypes of Sdc1 null (Sdc1-/-) mice were traced to an exaggerated innate immune response in the liver and a deficiency in pro-survival Akt signaling in hepatocytes and hepatocyte proliferation, which led to amplification of liver damage. Administration of purified Sdc1 or heparan compounds containing 2-O-sulfate motifs rescued Sdc1-/- mice from AILI by inhibiting innate immune responses, and by potentiating hepatocyte proliferation and liver repair. Furthermore, HS showed a significantly prolonged therapeutic efficacy as compared to N-acetylcysteine (NAC), the clinical antidote for APAP overdose. These findings suggest that Sdc1 and HS, either alone or in combination with NAC, could provide a new therapeutic strategy to combat AILI, especially in treating patients admitted after NAC treatment is no longer effective. Based on these preliminary data, we propose that Sdc1 is a critical endogenous factor that halts the perpetuation of liver injury and facilitates liver repair in AILI. This hypothesis will be tested in 3 specific aims. Aim 1 will define how Sdc1 is released from hepatocytes during AILI and establish that discrete structural motifs in Sdc1 HS provide protection against AILI. Aim 2 will elucidate the biological mechanisms of how Sdc1 halts the progression of AILI. Aim 3 will determine how Sdc1 enhances hepatocyte proliferation and facilitates liver repair in AILI. These studies are expected to establish a new integrated pathway in liver injury and repair.