Chamulitrat Walee, Zhang Wujuan, Xu Weihong, Pathil Anita, Setchell Kenneth, Stremmel Wolfgang
Department of Internal Medicine IV, University Heidelberg Hospital Heidelberg, Germany.
Front Physiol. 2012 Feb 20;3:24. doi: 10.3389/fphys.2012.00024. eCollection 2012.
It has been long known that hepatic synthesis of phosphatidylcholine (PC) is depressed during acute such as carbon tetrachloride-induced liver injury. Anti-hepatotoxic properties of PC as liposomes have been recognized for treatment of acute liver damage. Ursodeoxycholate (UDCA) is a known hepatoprotectant in stabilizing cellular membrane. For therapeutic management of liver injury, we coupled UDCA with a phospholipid known as ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE). UDCA-LPE has been shown to first-in-class hepatoprotectant being superior to UDCA or PC. It inhibits mitochondrial damage and apoptosis, elicits survival signaling pathway, and promotes regeneration of hepatocytes. We herein report that a unique contribution of UDCA-LPE in increasing concentrations of PC in vitro and in vivo. UDCA-LPE-treated hepatocytes contained significantly increased PC levels. UDCA-LPE underwent the hydrolysis to LPE which was not the precursor of the increased PC. The levels of PC in the liver and blood were increased rapidly after intraperitoneally administration UDCA-LPE, and were found to be sustained even after 24 h. Among PC synthesis genes tested, UDCA-LPE treatment of mouse hepatocytes increased transcription of CDP-diacylglycerol synthase 1 which is an enzyme catalyzing phosphatidic acid to generate intermediates for PC synthesis. Thus, UDCA-LPE as a hepatoprotectant was able to induce synthesis of protective PC which would supplement for the loss of PC occurring during acute liver injury. This property has placed UDCA-LPE as a candidate agent for therapy of acute hepatotoxicity such as acetaminophen poisoning.
长期以来，人们已知在急性肝损伤（如四氯化碳诱导的肝损伤）期间，肝脏中磷脂酰胆碱（PC）的合成会受到抑制。PC作为脂质体的抗肝毒性特性已被认可用于治疗急性肝损伤。熊去氧胆酸（UDCA）是一种已知的肝细胞保护剂，可稳定细胞膜。为了对肝损伤进行治疗管理，我们将UDCA与一种名为熊去氧胆酰溶血磷脂酰乙醇胺（UDCA-LPE）的磷脂偶联。已证明UDCA-LPE是一流的肝细胞保护剂，优于UDCA或PC。它抑制线粒体损伤和细胞凋亡，引发生存信号通路，并促进肝细胞再生。我们在此报告UDCA-LPE在体外和体内增加PC浓度方面的独特作用。经UDCA-LPE处理的肝细胞中PC水平显著增加。UDCA-LPE水解为LPE，但LPE不是增加的PC的前体。腹腔注射UDCA-LPE后，肝脏和血液中的PC水平迅速升高，甚至在24小时后仍保持升高。在所测试的PC合成基因中，用UDCA-LPE处理小鼠肝细胞可增加CDP-二酰甘油合酶1的转录，该酶催化磷脂酸生成PC合成的中间体。因此，UDCA-LPE作为一种肝细胞保护剂能够诱导保护性PC的合成，以补充急性肝损伤期间发生的PC损失。这一特性使UDCA-LPE成为治疗急性肝毒性（如对乙酰氨基酚中毒）的候选药物。
