In the fibrotic liver, hepatic stellate cells (HSC) produce large amounts of
collagen and secrete variety of mediators that promote development of
fibrosis in this organ. Therefore, these cells are considered an attractive target for antifibrotic
therapies. We incorporated the bioactive
lipid dilinoleoylphosphatidylcholine (DLPC) into the membrane of
liposomes, and then we evaluated its effect on hepatic stellate cell activation and
liver fibrosis. To target DLPC-
liposomes to HSC,
human serum albumin modified with
mannose 6-phosphate (M6P-HSA) was coupled to the surface of these
liposomes. In vitro, the effects of the carrier were determined in primary cultures of HSC, Kupffer cells, and liver endothelial cells using real-time reverse transcription-polymerase chain reaction. In vivo DLPC-
liposomes were tested in bile duct-ligated rats. Targeted M6P-HSA-DLPC-liposomes and DLPC-
liposomes significantly reduced gene expression levels for
collagen 1alpha1, alpha-smooth muscle actin (alpha-SMA), and
transforming growth factor-beta (
TGF-beta) in cultured HSC. In fibrotic livers, DLPC-
liposomes decreased gene expression for
TGF-beta and
collagen 1alpha1 as well as alpha-SMA and
collagen protein expression. In contrast, M6P-HSA-DLPC-liposomes enhanced expression of profibrotic and proinflammatory genes in vivo. In cultured Kupffer and endothelial cells M6P-HSA
liposomes influenced the expression of proinflammatory genes. Both types of
liposomes increased hepatocyte
glycogen content in fibrotic livers, indicating improved functionality of the hepatocytes. We conclude that DLPC-containing
liposomes attenuate activation of cultured HSC. In fibrotic livers, M6P-HSA-mediated activation of Kupffer and endothelial cells probably counteracts this beneficial effect of DLPC-
liposomes. Therefore, these bioactive
drug carriers modulate the activity of all liver cells during
liver fibrosis.