Low density lipoprotein receptor-related protein 1 modulates the proliferation and migration of human hepatic stellate cells

Human hepatic stellate cells (HHSCs) proliferation and migration play a key role in the pathogenesis of liver inflammation and fibrogenesis. Low density lipoprotein receptor‐related protein (LRP1) is an endocytic receptor involved in intracellular signal transduction. The aim of this work was to analyse the role of low density lipoprotein receptor‐related protein (LRP1) in HHSCs proliferation and migration and the mechanisms involved. Human LRP1 deficient‐HHSCs were generated by nucleofecting the line HHSCs with siRNA anti‐LRP1. HHSCs DNA synthesis was measured by [³H]‐thymidine incorporation and cell cycle progression by flow cytometry after annexin V and iodure propidium staining. Cell migration was assessed using a wound repair model system. LRP1 expression and extracellular matrix‐regulated kinase (ERK1,2) phosphorylation were analysed by Western blot analysis. Transforming growth factor‐β (TGF‐β) extracellular levels were analysed by ELISA. siRNA‐antiLRP1 treatment almost completely inhibited LRP1 mRNA and protein expression. LRP1 deficient HHSCs showed higher proliferative response (172 ± 19 vs. 93 ± 8 [³H]‐thymidine incorporation; 78.68% vs. 82.69% in G0/G1, 21.32% vs. 17.30% in G2/S) and higher migration rates than control HHSCs. LRP1 deficient cells showed higher levels of phosphorylated ERK1,2. TGF‐β extracellular levels were threefold higher in LRP1‐deficient than in control HHSCs cells. These results demonstrate that LRP1 regulates HHSCs proliferation and migration through modulation of ERK1,2 phosphorylation and TGF‐β extracellular levels. These results suggest that HHSCs‐LRP1 may play a key role in the modulation of factors determining hepatic fibrosis. J. Cell. Physiol. 227: 3528–3533, 2012. © 2012 Wiley Periodicals, Inc.