HB-EGF调控PPAR-α/UCP2信号改善肝脏能量代谢减轻脓毒症肝损伤的研究

Liver injury, usually occurring at early stage of sepsis, introduces the subsequent development of multiple organ failure. It has been well recognized that the improvement of hepatic energy metabolism can effectively alleviate sepsis-induced liver injury. Previously, we have found that the substance heparin binding epidermal like growth factor (HB-EGF) improves the hepatic energy metabolism in mouse developing sepsis-induced liver injury. However, the mechanism of how HB-EGF working requires the further study.The mitochondrial carrier protein uncoupling protein 2 (UCP2) plays a key role during hepatic energy metabolism. UCP2 is mainly regulated by the Peroxisome proliferator receptor-α (PPAR-α) transcriptionally in the mitochondria during sepsis. In our research, we have found that the expression of PPAR-α was up-regulated by HB-EGF in liver of septic mice. Collectively, we hypothesize that HB-EGF alleviates the sepsis-induced liver injury through it improving the hepatic energy metabolism by regulating the PPAR-α/UCP2 signal . The PPAR-α gene knockout mice will be employed in vivo (induced liver injury model) and in vitro (cell model) experiments to test the hypothesis. The findings in the project will advance our knowledge on the mechanism of sepsis-induced liver injury, and shall provide new protection strategy for sepsis-induced liver injury.

肝损伤是脓毒症患者常见的并发症，也是导致多器官功能衰竭的重要因素，研究证实改善肝脏能量代谢有助于减轻脓毒症肝损伤。申请者前期研究发现具有调节能量代谢功能的肝素结合表皮生长因子样生长因子（HB-EGF）对脓毒症肝损伤具有保护作用，但机制尚不清楚。解偶联蛋白2（UCP2）是线粒体内膜上的一种载体蛋白，参与肝脏的能量代谢，而过氧化物酶体增殖物激活受体α（PPAR-α）是UCP2的转录调控蛋白。申请者前期实验发现HB-EGF可上调脓毒症小鼠肝脏PPAR-α的表达。因此，申请者提出了“HB-EGF调控PPAR-α/UCP2信号改善肝脏能量代谢减轻脓毒症肝损伤”的假说。本项目拟采用PPAR-α基因敲除小鼠的脓毒症肝损伤模型和离体细胞模型来验证该假说，为寻找脓毒症肝损伤的防治策略提供理论依据。

HB-EGF作为一种细胞保护因子对多种组织器官起保护作用，并表现出减轻脓毒症相关损伤的潜能。本研究项目致力于脓毒症肝损伤的防治，我们从肝脏能量代谢的角度出发，通过PPAR-α/UCP2信号来探讨HB-EGF在脓毒症肝损伤过程中的作用及机制。我们首先建立了稳定的脓毒症肝损伤小鼠模型，证实了HB-EGF可减轻脓毒症小鼠的肝损伤，改善脓毒症小鼠肝功能并提高其存活率；检测了脓毒症小鼠血清HB-EGF、肝脏PPAR-α水平等指标的变化，表明HB-EGF和PPAR-α参与了脓毒症肝损伤的病理生理过程；从肝脏能量代谢角度的研究表明HB-EGF可下调脓毒症小鼠血清UCP2水平并增加肝脏组织ATP水平，并初步阐明了HB-EGF可通过调控PPAR-α对肝细胞的增殖产生影响；后续PPAR-α基因敲除小鼠的相关实验将提供更多数据。本研究项目将为脓毒症肝损伤的防治提供一种新的视角、方法及理论依据。