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

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.

Plasma membrane phospholipase A2controls hepatocellular fatty acid uptake and is responsive to pharmacological modulation: implications for nonalcoholic steatohepatitis

“…Moreover, as discussed above, the competition of UDCA‐LPE with PC may also induce the displacement of iPLA 2 β from the DRM‐PM‐localized fatty acid uptake complex, triggering its disintegration. The advantage of this conjugate compared with that of other iPLA 2 β inhibitors is its nontoxicity, because its breakdown products are degraded by the cellular metabolic machinery (11, 12). Thus, the development of an ingestible form of UDCA‐LPE and a validation of its clinical efficacy would offer a viable, potential treatment strategy for NASH.…”

“…Mouse hepatocytes were isolated from 7‐ to 10‐wk‐old male wild‐type or iPLA 2 β‐null mice (kind gift from Dr. John Turk, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA) by using a 2‐step collagenase perfusion technique and purified by Percoll (17‐0891‐01; PAA, Cölbe, Germany) as described previously (12). Freshly isolated hepatocytes were plated and cultured for 16 h in M199 medium containing Hanks' salts and l ‐glutamine (E15‐838; PAA) supplemented with 1% penicillin and streptomycin (P11‐010; PAA), 100 nM dexamethasone (IO516; Sigma‐Aldrich), 0.5 nM insulin (D2915; Sigma‐Aldrich), and 4% neonatal calf serum (A15‐315; PAA).…”

“…We synthesized the bile acid-phospholipid conjugate ursodeoxycholate-lysophosphatidylethanolamide (UDCA-LPE), which is taken up by hepatocytes via bile acid carriers and remains intact in the cell to exert its effects (11,12). UDCA-LPE inhibited inflammation and apoptosis, as well as fat accumulation in the liver, in mouse models of hepatic injury and steatosis (13,14) through unknown molecular mechanisms.…”

Oleic Acid Protects against Hepatic Ischemia and Reperfusion Injury in Mice by Inhibiting AKT/mTOR Pathways

“…Ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE), a novel anti-inflammatory agent with hepatoprotective effects, was developed by Chamulitrat et al by coupling UDCA with a phospholipid. This drug inhibits mitochondrial damage and apoptosis, induces the survival signaling pathway, and promotes the regeneration of hepatocytes [8]. The mechanisms underlying the protective effects of this drug include shifting FA pools toward monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA), attenuating hepatofibrogenesis by impairment of TGF-β1/Smad2/3 signaling [9] and inherent, pronounced anti-inflammatory effects [10,11].…”

Recent Insights into Treatment of Non-Alcoholic Steatohepatitis

“…Nonetheless, bile acid conjugates have recently been tested such as Ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE) that has been used on high-fat diet mouse model and showed a a modification in fatty acid metabolism, hepatoprotective and anti-inflammatory effects [103][104][105][106]. Moreover, it has been shown that UDCA-LPE modulates flawed fatty acid metabolism in mice fed High-Fat Diet (HFD) thus restoring altered lipid profiles and has pronounced anti-inflammatory effects [107].…”