Liver X receptors balance lipid stores in hepatic stellate cells through Rab18, a retinoid responsive lipid droplet protein

摘要: Liver X receptors (LXRs) are determinants of hepatic stellate cell (HSC) activation and liver fibrosis. Freshly isolated HSCs from Lxrαβ−/− mice have increased lipid droplet (LD) size, but the functional consequences this unknown. Our aim was to determine whether LXRs link cholesterol retinoid storage in how impacts activation. Primary wild-type were profiled by gene array during vitro Lipid content quantified high-performance liquid chromatography mass spectroscopy. treated with nuclear receptor ligands, transfected small interfering RNA plasmid constructs, analyzed immunocytochemistry. retinyl esters. The increase drives intrinsic retinoic acid signaling, occurs more rapidly HSCs. We identify Rab18 as a novel acid-responsive, LD-associated protein that helps mediate mRNA, protein, membrane insertion Both guanosine triphosphatase activity isoprenylation required for LD loss induction markers. These phenomena accelerated HSCs, where there is greater flux. Conversely, knockdown retards culture blocks activation, just like mutants. also induced acute injury vivo. Conclusion: Retinoid metabolism linked cells Rab18. overload explain profibrotic phenotype mice, we establish pivotal role GTPase Interference may significant therapeutic benefit ameliorating (Hepatology 2015;62:615–626