Hepatic stellate cell lipid droplets: a specialized lipid droplet for retinoid storage

Abstract

The majority of retinoid (vitamin A and its metabolites) present in the body of a healthy vertebrate is contained within lipid droplets present in the cytoplasm of hepatic stellate cells (HSCs). Two types of lipid droplets have been identified through histological analysis of HSCs within the liver: smaller droplets bounded by a unit membrane and larger membrane-free droplets. Dietary retinoid intake but not triglyceride intake markedly influences the number and size of HSC lipid droplets. The lipids present in rat HSC lipid droplets include retinyl ester, triglyceride, cholesteryl ester, cholesterol, phospholipids and free fatty acids. Retinyl ester and triglyceride are present at similar concentrations, and together these two classes of lipid account for approximately three-quarters of the total lipid in HSC lipid droplets. Both adipocyte-differentiation related protein and TIP47 have been identified by immunohistochemical analysis to be present in HSC lipid droplets. Lecithin:retinol acyltransferase (LRAT), an enzyme responsible for all retinyl ester synthesis within the liver, is required for HSC lipid droplet formation, since Lrat-deficient mice completely lack HSC lipid droplets. When HSCs become activated in response to hepatic injury, the lipid droplets and their retinoid contents are rapidly lost. Although loss of HSC lipid droplets is a hallmark of developing liver disease, it is not known whether this contributes to disease development or occurs simply as a consequence of disease progression. Collectively, the available information suggests that HSC lipid droplets are specialized organelles for hepatic retinoid storage and that loss of HSC lipid droplets may contribute to the development of hepatic disease.

Figures

Fig. 1

Chemical structures for the most abundant and important retinoids present in the body. All-trans-retinol, which by definition is vitamin A, is routinely referred to simply as retinol. Retinyl esters are retinoid storage forms. Outside of the eye, the preponderance of retinyl ester exists as the all-trans-isomer. It is this retinoid species that is stored in the lipid droplets of hepatic stellate cells. 11-Cis-retinal serves as the chromophore for the visual pigment rhodopsin. All-trans- and 9-cis-retinoic acids are transcriptionally active retinoids. 13-Cis-retinoic acid is a naturally occurring retinoid that lacks the potent transcriptional activity of the all-trans- and 9-cis-isomer. However, this retinoid species has proven to be clinically effective for treating skin disease (clinically it is referred to as isotretinoin or Accutane).

Fig. 2

Hepatic stellate cell lipid droplets present in a biospy obtained from a human liver. The image shows the characteristic lipid droplets (LD) found in hepatic stellate cells (SC). For this electron micrograph of a human hepatic stellate cell, the nucleus (N) is compressed by the surrounding lipid droplets and very little cell cytoplasm within the hepatic stellate cell can be seen. Adjoining the hepatic stellate cell are two hepatocytes (H).

Fig. 3

Fluorescence micrograph of an unfixed section showing the characteristic retinoid autofluorescence (the lightened regions) present in the lipid droplets of hepatic stellate cells of male wild type mice that had been maintained throughout life on a retinoid-containing control diet.

Fig. 4

The hepatic stellate cells of Lrat−/− mice lack lipid droplets that are a morphologic hallmark of these cells. Liver sections were prepared from 3-month-old male wild type (WT) and Lrat−/− mice. The electron micrographs show the presence of characteristic retinyl ester-containing lipid droplets in hepatic stellate cells in wild type mice (left panel) and their absence in livers from Lrat−/− mice (right panel). The arrows indicate the presence (WT) and absence (Lrat−/−) of lipid droplets in hepatic stellate cells. The large adjoining cells are hepatocytes. Taken from [32].