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Increased activation of CD95/Fas by Fas ligand in viral hepatitis and autoimmunity is involved in pathogenesis of fulminant hepatitis and liver failure. We designed a bile-acid phospholipid conjugate ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE with LPE containing oleate at the sn-1) as a hepatoprotectant that was shown to protect against fulminant hepatitis induced by endotoxin. We herein further assessed the ability of UDCA-LPE to prevent death receptor CD95/Fas-induced fulminant hepatitis. C57BL/6 mice were intravenously administered with CD95/Fas agonistic monoclonal antibody (Jo-2) with or without 1 h pretreatment with 50 mg/kg UDCA-LPE. Jo-2 administration caused massive hepatocyte damage as seen by histology, and this was associated with a significant decrease in hepatic phosphatidylcholine (PC), lysoPC, and lysophosphatidylethanolamine levels. By histology, UDCA-LPE pretreatment improved hepatocyte damage and restored the loss of these phospholipids in part by a mechanism involving an inhibition of cytosolic phospholipaseA2 expression. Accordingly, Jo-2 treatment increased hepatic expression of cleaved caspase 8, caspase 3, and poly (ADP-Ribose) polymerase-1, and on the other hand decreased that of anti-apoptotic cellular FLICE-inhibitory protein. UDCA-LPE pretreatment was able to reverse all these changes. Moreover, UDCA-LPE attenuated inflammatory response by lowering the levels of Jo-2-induced proinflammatory cytokines TNF-α, IL-6, and IL-1β in liver and serum. UDCA-LPE was also able to decrease the levels of stimulated Th1/Th17 cytokines in Jo-2-primed isolated splenocytes. Taken together, UDCA-LPE exhibited potent anti-inflammatory effects against CD95/Fas-induced fulminant hepatitis.

Nonalcoholic fatty liver disease (NAFLD) is the most common progressive liver disease worldwide. Currently, there is no satisfying treatment for NAFLD. Research progress in fatty acid bile acid conjugates (FABACs) and ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE), which are two novel liver targeted drugs with anti-NAFLD effects, is reviewed. FABACs, which reduce liver fat in patients with NAFLD induced by high-fat diet by regulating lipid metabolism, have been proved effective in preventing and treating NAFLD. The safety and efficacy of FABACs in NAFLD patients have been confirmed in a phase II, randomized, double-blind, placebo-controlled trial. UDCA-LPE can not only reduce liver fat in NAFLD patients, but also inhibit mitochondrial damage and apoptosis and promote hepatocyte regeneration, with a marked anti-inflammatory effect during the development of NAFLD. Therefore, FABACs and UDCA-LPE hold promise for preventing and treating NAFLD.