The synthetic bile acid-phospholipid conjugate ursodeoxycholyl lysophosphatidylethanolamide suppresses TNFα-induced liver injury.

Excessive apoptosis and leukocyte-dependent inflammation mediated by pro-inflammatory cytokines, such as TNFα, are cardinal features of acute liver injury. This study evaluated the ability of the newly designed bile acid-phospholipid conjugate ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE) to protect from hepatocellular injury in comparison to the known hepatoprotectant ursodeoxycholic acid (UDCA) and phosphatidylcholine (PC). Anti-apoptotic and anti-inflammatory properties of UDCA-LPE were evaluated after TNFα treatment of embryonic human hepatocyte cell line CL48 as well as of primary human hepatocytes. Acute liver injury was induced in C57BL/6 mice with d-galactosamine/lipopolysaccharide (GalN/LPS) in order to determine in vivo efficacy of the conjugate. UDCA-LPE inhibited TNFα-induced apoptosis and inflammation in hepatocytes in vitro and markedly ameliorated GalN/LPS-mediated fulminant hepatitis in mice, whereas UDCA or PC failed to show protection. The conjugate was able to decrease injury-induced elevation of phospholipase A(2) activity as well as its product lysophosphatidylcholine. Analysis of hepatic gene expression showed that UDCA-LPE treatment led to favourable inhibitory effects on expression profiles of key pro-inflammatory cytokines and chemokines, which are crucial for leukocyte recruitment and activation thereby inhibiting chemokine-mediated aggravation of parenchymal damage. Thus, UDCA-LPE as a synthetic bile acid-phospholipid conjugate may represent a potent anti-inflammatory agent that is more effective than UDCA and PC for treatment of liver diseases.

Pathil A ，Warth A ，Chamulitrat W ，Stremmel W ... -  《-》

Comparison of different bile acid-phospholipid conjugates in acute hepatitis.

The bile acid-phospholipid conjugate ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE) is a promising novel compound with profound hepatoprotective functions in vitro and in vivo. Because of high costs of LPE synthesis from hydrolysis of phosphatidylethanolamide (PE), costs for UDCA-LPE synthesis for in vivo and human use can become quite high. In this study, we evaluated whether ursodeoxycholyl phosphatidylethanolamide (udca-pe), which is more cost-effective, could replace udca-lpe in terms of protection from hepatocellular injury. Anti-apoptotic and anti-inflammatory properties of UDCA-PE and UDCA-LPE were compared in TNFα/cyclohexamide (CHX)-treated HepG2 cells as well as in a mouse model of d-galactosamine/lipopolysaccharide (Gal/LPS)-induced acute liver injury. Ursodeoxycholyl lysophosphatidylethanolamide inhibited TNFα/CHX-induced apoptosis in HepG2 cells in a dose-dependent manner and markedly ameliorated Gal/LPS-mediated fulminant hepatitis in mice. In contrast, UDCA-PE showed weaker hepatoprotective functions at low concentrations, and protection was lost at higher dosage. Analysis of hepatic gene expression showed that both conjugates significantly reduced Gal/LPS-mediated expression of chemoattractants, such as monocyte chemotactic protein 1 (MCP1) and RANTES. These inhibitory effects by UDCA-PE were transient while those by UDCA-LPE were sustained in attenuating expression of inflammatory MCP1 and RANTES expression. Our data underline the superiority of UDCA-LPE compared to UDCA-PE in ameliorating acute liver inflammation. This indicates the significance of the lyso-functional group of bile acid conjugate for optimal hepatoprotection and reduction in inflammation in vivo.

Pathil A ，Warth A ，Chamulitrat W ，Stremmel W ... -  《-》

Anti-inflammatory properties of ursodeoxycholyl lysophosphatidylethanolamide in endotoxin-mediated inflammatory liver injury.

Ludwig JM ，Zhang Y ，Chamulitrat W ，Stremmel W ，Pathil A ... -  《PLoS One》

Ursodeoxycholyl Lysophosphatidylethanolamide modifies aberrant lipid profiles in NAFLD.

Hepatic fat accumulation with disturbed lipid homoeostasis is a hallmark of nonalcoholic fatty liver disease (NAFLD). The bile acid phospholipid conjugate Ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE) is a novel anti-inflammatory agent with hepatoprotective effects in murine high-fat-diet (HFD)-induced NAFLD. The aim of this work was to study changes in the hepatic lipidome due to UDCA-LPE. High fat diet mouse model, mass spectometry, RT-PCR. Hepatic lipid extracts of HFD mice were analysed by mass spectrometry. The results determined higher levels of total, saturated, mono- and diunsaturated fatty acids (FA) in HFD mice, which were decreased by UDCA-LPE predominantly by the reducing the most abundant FA species palmitic acid and oleic acid. Unlike other FA species, levels of long-chain polyunsaturated fatty acids (LCPUFA), which are composed of arachidonic acid (ARA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), were increased in HFD mice upon UDCA-LPE treatment, mainly due to elevated hepatic ARA pools. Analysis of hepatic phospholipids species showed a decrease in total phosphatidylcholine (PC), especially monounsaturated PC (PUFA-PC) levels in HFD mice. Loss of total PC was reversed due to UDCA-LPE by increasing hepatic PUFA-PC pools. Gene expression analysis showed that UDCA-LPE upregulated PPARα, a key transcriptional regulator of fatty acid oxidation, as well as downstream target genes CPT1α and AOX, which are crucially involved in mitochondrial and peroxisomal fatty acid oxidation. UDCA-LPE modulates defective fatty acid metabolism during experimental NAFLD thereby restoring altered lipid profiles in addition to its pronounced anti-inflammatory effects. Thus, UDCA-LPE may be a promising drug candidate for the management of NAFLD.

Pathil A ，Liebisch G ，Okun JG ，Chamulitrat W ，Schmitz G ，Stremmel W ... -  《-》

Bile salt-phospholipid conjugate ursodeoxycholyl lysophosphatidylethanolamide as a hepatoprotective agent.

Chamulitrat W ，Burhenne J ，Rehlen T ，Pathil A ，Stremmel W ... -  《-》