Abstract
Retinoids are mostly stored as retinyl esters in hepatic stellate cells (HSCs) through esterification of retinol and fatty acid, catalyzed by lecithin-retinol acyltransferase (LRAT). This study is designated to address how retinyl esters are mobilized in liver injury for tissue repair and wound healing. Initially, we speculated that acute inflammatory cytokines may act as injury signal to mobilize retinyl esters by down-regulation of LRAT in HSCs. By examining a panel of cytokines we found interleukin-1 (IL-1) can potently down-regulate mRNA and protein levels of LRAT, resulting in mobilization of retinyl esters in primary rat HSCs. To simulate the microenvironment in the space of Disse, HSCs were embedded in three-dimensional extracellular matrix, by which HSCs retaine quiescent phenotypes, indicated by up-regulation of LRAT and accumulation of lipid droplets. Upon IL-1 stimulation, LRAT expression went down together with mobilization of lipid droplets. Secreted factors from Kupffer cells were able to suppress LRAT expression in HSCs, which was neutralized by IL-1 receptor antagonist. To explore the underlying mechanism we noted that the stability of LRAT protein is not significantly regulated by IL-1, indicating the regulation is likely at transcriptional level. Indeed, we found that IL-1 failed to down-regulate recombinant LRAT protein expressed in HSCs by adenovirus, while transcription of endogenous LRAT was promptly decreased. Following liver damage, IL-1 was promptly elevated in a close pace with down-regulation of LRAT transcription, implying their causative relationship. After administration of IL-1, retinyl ester levels in the liver, as measured by LC/MS/MS, decreased in association with down-regulation of LRAT. Likewise, IL-1 receptor knockout mice were protected from injury-induced down-regulation of LRAT. In summary, we identified IL-1 as an injury signal to mobilize retinyl ester in HSCs through down-regulation of LRAT, implying a mechanism governing transition from hepatic injury to wound healing.
