Abstract
AimEndotoxin-mediated liver inflammation is a key component of many acute and chronic liver diseases contributing to liver damage, fibrosis and eventually organ failure. Here, we investigated ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE), a synthetic bile acid-phospholipid conjugate regarding its anti-inflammatory and anti-fibrogenic properties.MethodsAnti-inflammatory properties of UDCA-LPE were evaluated in a mouse model of D-galactosamine/lipopolysaccharide (GalN/LPS)-induced acute liver injury, LPS treated RAW264.7 macrophages and murine primary Kupffer cells. Furthermore, anti-inflammatory and anti-fibrotic effects of UDCA-LPE were studied on primary hepatic stellate cells (HSC) incubated with supernatant from LPS±UDCA-LPE treated RAW264.7 cells.ResultsUDCA-LPE ameliorated LPS-induced increase of IL-6, TNF-α, TGF-β, NOX-2 in the GalN/LPS model by up to 80.2% for IL-6. Similarly, UDCA-LPE markedly decreased the expression of inflammatory cytokines IL-6, TNF-α and TGF-β as well as the chemokines MCP1 and RANTES in LPS-stimulated RAW 264.7 cells. Anti-inflammatory effects were also observed in primary murine Kupffer cells. Mechanistic evaluation revealed a reversion of LPS-activated pro-inflammatory TLR4 pathway by UDCA-LPE. Moreover, UDCA-LPE inhibited iNOS and NOX-2 expression while activating eNOS via phosphorylation of AKT and pERK1/2 in RAW264.7 cells. HSC treated with conditioned medium from LPS±UDCA-LPE RAW264.7 cells showed lower fibrogenic activation due to less SMAD2/3 phosphorylation, reduced expression of profibrogenic CTGF and reduced pro-inflammatory chemokine expression.ConclusionIn the setting of endotoxin-mediated liver inflammation, UDCA-LPE exerts profound anti-inflammatory and anti-fibrotic effect implying a promising potential for the drug candidate as an experimental approach for the treatment of acute and chronic liver diseases.
Highlights
Liver inflammation is a key component in many acute and chronic liver diseases leading to parenchymal damage and progressing to fibrosis, liver cancer and eventually to liver failure [3, 4]
Mechanistic evaluation revealed a reversion of LPS-activated pro-inflammatory Toll-Like receptor-4 (TLR4) pathway by UDCA-LPE
hepatic stellate cells (HSC) treated with conditioned medium from LPS±UDCALPE RAW264.7 cells showed lower fibrogenic activation due to less SMAD2/3 phosphorylation, reduced expression of profibrogenic connective tissue growth factor (CTGF) and reduced pro-inflammatory chemokine expression
Summary
Liver inflammation is a key component in many acute and chronic liver diseases leading to parenchymal damage and progressing to fibrosis, liver cancer and eventually to liver failure [3, 4]. TLR4 is expressed on all cells but shows the highest expression on resident liver macrophages, the Kupffer cells (KC), which after TLR4 pathway activation primarily drive the inflammatory cascade by secretion of pro-inflammatory cytokines and chemokines, production of reactive oxygen species (ROS), and synthesis of nitric oxide (NO) leading to dysregulation of liver homeostasis [5,6,7]. Within this inflammatory environment, quiescent hepatic stellate cells (HSC) undergo activation, facilitate the inflammatory reaction and cause liver fibrosis by secretion pro-fibrogenic growth factors such as connective tissue growth factor (CTGF) and extracellular matrix. UDC-LPE demonstrated protective effects in endotoxin-mediated acute liver failure and NASH mouse models [13, 14]
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