Retinoid storage in hepatic stellate cells

Abstract

The liver is the main site of retinoid storage in the body. Within the liver, retinyl esters are hydrolyzed to retinol within hepatocytes and then may be secreted from the liver into the circulation bound to retinol‐binding protein (RBP) or may be re‐esterified by lecithin:retinol acyl transferase (LRAT) to form retinyl ester. Retinyl esters are then stored within the lipid droplets of hepatic stellate cells. We have previously reported that LRAT −/− mice have impaired absorption and storage of retinyl esters and have hepatic stellate cells devoid of their characteristic lipid droplets. Immunohistochemical studies of mouse liver using a monoclonal antibody against LRAT show expression primarily in hepatic stellate cells. We propose that LRAT is necessary for the formation of the lipid droplet by the stellate cell. To determine how retinoids are released from the lipid droplet, histologic examination of livers of RBP−/− mice was performed. In 18 month‐old RBP−/− mice, hepatic stellate cell lipid droplets were markedly enlarged. In 31 month‐old RBP−/− mice, numerous lipogranulomas, composed of lipid laden macrophages, were identified. EPON‐embedded thin sections and electron microscopy showed that the lipogranulomas were centered around hepatic stellate cells. Minimal steatosis of the RBP−/− livers was present. We propose that in the absence of RBP, hepatic stellate cell lipid droplets become distended and leak lipid eliciting a granulomatous reaction. The findings suggest that LRAT is necessary for lipid droplet formation and RBP is involved in mobilization of retinyl esters from lipid droplets in hepatic stellate cells. This work was supported by grants R01 DK061310, DK068436 and DK079221.