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Interleukin-1 as an Injury Signal Mobilizes Retinyl Esters in Hepatic Stellate Cells through Down Regulation of Lecithin Retinol Acyltransferase
- Source :
- PLoS ONE, Vol 6, Iss 11, p e26644 (2011), PLoS ONE
- Publication Year :
- 2011
- Publisher :
- Public Library of Science (PLoS), 2011.
-
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.
- Subjects :
- medicine.medical_specialty
Anatomy and Physiology
Non-Clinical Medicine
Retinoic acid
Down-Regulation
lcsh:Medicine
Gastroenterology and Hepatology
Biology
Proinflammatory cytokine
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Immune Physiology
Internal medicine
Lipid droplet
medicine
Animals
lcsh:Science
Nutrition
030304 developmental biology
0303 health sciences
Multidisciplinary
lcsh:R
Retinol
Vitamins
Rats
Endocrinology
Liver
chemistry
030220 oncology & carcinogenesis
Acyltransferase
Hepatic stellate cell
Cytokines
Medicine
lcsh:Q
Lecithin retinol acyltransferase
Signal transduction
Acyltransferases
Interleukin-1
Signal Transduction
Research Article
Subjects
Details
- ISSN :
- 19326203
- Volume :
- 6
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....bf1ff5f4ee28b1d07a0d9b759f0e141a