Abstract
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.
Highlights
Phospholipids including lecithins and phosphatidylcholine (PC) have been used and tested in humans for treatment of liver disease since the 1970s (Wallnofer and Hanusch, 1973)
Ursodeoxycholyl lysophosphatidylethanolamide is a first-in-class hepatoprotectant being superior to UDCA or PC capable of inhibiting hepatocellular apoptosis (Chamulitrat et al, 2009) and inflammation in vivo under acute liver injury (Pathil et al, 2011a)
PC controls liver homeostasis by membrane stabilization and the loss of PC levels results in an on-set of development of liver disease. It is of a question whether UDCA-LPE could increase PC to replenish PC for cytoprotection
Summary
Phospholipids including lecithins and phosphatidylcholine (PC) have been used and tested in humans for treatment of liver disease since the 1970s (Wallnofer and Hanusch, 1973). Total phospholipids in hepatic microsomes (Sgoutas, 1967), endoplasmic reticulum (James et al, 1982), and plasma membrane (Camacho and Rubalcava, 1984) are markedly depressed following CCl4 administration of experimental animals. This is due to decreased syntheses of both phospholipids and triglycerides readily observed 4–5 h after treatment (Gebhart and Brabec, 1985). It is conceivable that a supplementation of PC during acute liver injury replenishes www.frontiersin.org
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