10.6084/m9.figshare.5621041 Ming Chen Ming Chen Jiaxing Liu Jiaxing Liu Wenqi Yang Wenqi Yang Wenhua Ling Wenhua Ling Lipopolysaccharide mediates hepatic stellate cell activation by regulating autophagy and retinoic acid signaling Taylor & Francis Group 2017 autophagy BAMBI hepatic stellate cell liver fibrosis LPS retinoic acid signaling TGFB 2017-11-21 15:02:19 Dataset https://tandf.figshare.com/articles/dataset/Lipopolysaccharide_mediates_hepatic_stellate_cell_activation_by_regulating_autophagy_and_retinoic_acid_signaling/5621041 <p>Bacterial translocation and lipopolysaccharide (LPS) leakage occur at a very early stage of liver fibrosis in animal models. We studied the role of LPS in hepatic stellate cell (HSC) activation and the underlying mechanisms in vitro and in vivo. Herein, we demonstrated that LPS treatment led to a dramatic increase in autophagosome formation and autophagic flux in LX-2 cells and HSCs, which was mediated through the AKT-MTOR and AMPK-ULK1 pathway. LPS significantly decreased the lipid content, including the lipid droplet (LD) number and lipid staining area in HSCs; pretreatment with macroautophagy/autophagy inhibitors or silencing ATG5 attenuated this decrease. Furthermore, lipophagy was induced by LPS through the autophagy-lysosomal pathway in LX-2 cells and HSCs. Additionally, LPS-induced autophagy further reduced retinoic acid (RA) signaling, as demonstrated by a decrease in the intracellular RA level and <i>Rar</i> target genes, resulting in the downregulation of <i>Bambi</i> and promoting the sensitization of the HSC's fibrosis response to TGFB. Compared with CCl<sub>4</sub> injection alone, CCl<sub>4</sub> plus LPS injection exaggerated liver fibrosis in mice, as demonstrated by increased <i>Col1a1</i> (collagen, type I, α 1), <i>Acta2, Tgfb</i> and <i>Timp1</i> mRNA expression, ACTA2/α-SMA and COL1A1 protein expression, and Sirius Red staining area, which could be attenuated by injection of an autophagy inhibitor. LPS also reduced lipid content in HSCs in vivo, with this change being attenuated by chloroquine (CQ) administration. In conclusion, LPS-induced autophagy resulted in LD loss, RA signaling dysfunction, and downregulation of the TGFB pseudoreceptor <i>Bambi</i>, thus sensitizing HSCs to TGFB signaling.</p>