Hepatoprotectant Ursodeoxycholyl Lysophosphatidylethanolamide Increasing Phosphatidylcholine Levels as a Potential Therapy of Acute Liver Injury

Department of Internal Medicine IV, University Heidelberg Hospital Heidelberg, Germany.
Frontiers in Physiology (Impact Factor: 3.53). 02/2012; 3:24. DOI: 10.3389/fphys.2012.00024
Source: PubMed


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.

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    • "MSC exhibits additional anti-inflammatory properties, thus, may lead to an attenuated inflammatory response. Chamulitrat et al. (2012) suggest a derivative of ursodeoxycholic acid as possible novel treatment option. For the majority of individuals with fulminant ALF, however , a liver transplant (LTx) remains the only curative option. "

    Frontiers in Physiology 01/2014; 5:18. DOI:10.3389/fphys.2014.00018 · 3.53 Impact Factor
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    • "Cell lysates were subjected to lipid extraction in the presence of D 4 -UDCA as an internal standard. UDCA-LPE and UDCA concentrations in samples and standards were determined using a liquid chromatography mass spectrometer (Waters 2695 interfaced with a Quattro Micro; Waters, Milford, MA) (Chamulitrat et al., 2012). Fig. 1 "
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    ABSTRACT: Ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE) is hepatoprotectant in inhibiting apoptosis, inflammation, and hyperlipidemia in mouse models of non-alcoholic steatohepatitis (NASH). We herein studied the ability of UDCA-LPE to inhibit palmitate (Pal)-induced apoptosis in primary hepatocytes, and delineate cytoprotective mechanisms. We showed that lipoprotection by UDCA-LPE was mediated by adenosine 3', 5'-cyclic monophosphate (cAMP), and was associated with increases of triglycerides (TG) and phospholipids (PL). An inhibitor of cAMP-effector protein kinase A partially reversed protective effects of UDCA-LPE. Lipidomic analyses of fatty acids and PL composition revealed a shift of lipid metabolism from saturated Pal to mono- and polyunsaturated fatty acids, mainly, oleate, docosapentaenoate and docosahexaenoate. The latter two ω-3 fatty acids were particularly found in phosphatidylcholine and phosphatidylserine pools. The catalysis of Pal by stearoyl-CoA desaturase-1 (SCD-1) is a known mechanism for the channelling of Pal away from apoptosis. SCD-1 protein was upregulated during UDCA-LPE lipoprotection. SCD-1 knockdown of Pal-treated cells showed further increased apoptosis and the extent of UDCA-LPE protection was reduced. Thus, the major mechanism of UDCA-LPE lipoprotection involved a metabolic shift from toxic saturated towards cytoprotective unsaturated fatty acids in part via SCD-1. UDCA-LPE may thus be a therapeutic agent for treatment of NASH by altering distinct pools of fatty acids for storage into TG and PL, and the latter may protect lipotoxicity at the membrane levels.
    Molecular pharmacology 08/2013; 84(5). DOI:10.1124/mol.113.088039 · 4.13 Impact Factor
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    ABSTRACT: Excess hepatic fat accumulation leads to nonalcoholic steatohepatitis (NASH), a serious threat to health for which no effective treatment is available. However, the mechanism responsible for fatty acid uptake by hepatocytes remains unclear. Using the human hepatocyte-derived tumor cell line HepG2, we found that fatty acid influx is mediated by a heterotetrameric plasma membrane protein complex consisting of plasma membrane fatty acid-binding protein, caveolin-1, CD36, and calcium-independent membrane phospholipase A2 (iPLA2β). Blocking iPLA2β with the bile acid-phospholipid conjugate ursodeoxycholate-lysophosphatidylethanolamide (UDCA-LPE) caused the dissociation of the complex, thereby inhibiting fatty acid influx (IC50 47 μM), and suppressed the synthesis of all subunits through a reduction in lysophosphatidylcholine from 8.0 to 3.5 μmol/mg of protein and corresponding depletion of phosphorylated c-Jun N-terminal kinase. These findings were substantiated by an observed 56.5% decrease in fatty acid influx in isolated hepatocytes derived from iPLA2β-knockout mice. Moreover, steatosis and inflammation were abrogated by UDCA-LPE treatment in a cellular model of NASH. Thus, iPLA2β acts as an upstream checkpoint for mechanisms that regulate fatty acid uptake, and its inhibition by UDCA-LPE qualifies this nontoxic compound as a therapeutic candidate for the treatment of NASH.-Stremmel, W., Staffer, S., Wannhoff, A., Pathil, A., Chamulitrat, W. Plasma membrane phospholipase A2 controls hepatocellular fatty acid uptake and is responsive to pharmacological modulation: implications for nonalcoholic steatohepatitis.
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