Hormonal regulation of the class B scavenger receptors CD36 and SR-BI, in the rat liver.

Abstract

CD36 or fatty acid translocase (FAT) is an 88 kDa cell surface protein. It is characterised functionally as a Scavenger Receptor, and it is the founding member of the Class B subtype, which also includes the HDL receptor, Scavenger Receptor Class B-I (SR-BI). A common feature of all scavenger receptors is a broad binding specificity and many ligands have been identified for CD36. Of particular interest to this project are the metabolic ligands, such as native and modified lipoprotein particles and long chain fatty acids. In the rat, others have reported that CD36 is expressed in heart muscle, intestine, spleen, skeletal muscle, adipose tissue and testis. Previous work in our laboratory, using a new monoclonal antibody (mAb UA009), extended the distribution of CD36 to include the adrenal cortex, the ovary and the parenchymal cells of the liver. Furthermore it was noted that hepatocytes from female DA rats expressed considerably more CD36 than their male counterparts. The scope and objective of this project was to investigate the effects of gender on expression of CD36 in the liver, and to compare it with expression of SR-B1. Expression of CD36 was examined in vivo, in normal and experimentally manipulated female and male rats and mice, using immuno-histochemistry plus video-image analysis, quantitative Western blot and real-time PCR techniques. It was shown that female predominant expression of CD36 i) is specific to the liver, ii) occurs in many strains of laboratory rats, and iii) is also present in three mouse strains. Investigation of CD36 expression during post-natal development revealed that in neonates, the protein is not expressed by parenchymal cells of the liver. Although CD36 is expressed by hepatocytes from approx. 4 weeks of age, the adult pattern (female predominant) was not observed until the onset of puberty. No changes in the levels of SR-BI expression were observed during development. The role of hormones in regulating expression of CD36 was investigated by observing the effects of gonadectomy and supplementation with sex steroid hormones. Hepatic expression of CD36 was reduced by oophorectomy and increased by castration. Sexually dimorphic expression was restored by administration of estrogen or testosterone to gonadectomised females and males, respectively. Inhibition of gonadotropin release did not alter the effect of castration but the gender difference, and the response to gonadectomy, was reduced in growth hormone-deficient rats. In contrast, SR-BI was barely detectable in liver by immuno-histochemistry in either sex, although modest differences between females and males and changes in response to gonadectomy were observed in levels of Sr-bI/II transcripts. The results demonstrated the importance of the endocrine milieu in the regulation of CD36 expression by the liver. Although the initial acquisition of CD36 expression during postnatal development is sex steroid hormone independent, the sexually dimorphic adult pattern of expression coincides with the onset of puberty. The influence of sex steroids on hepatic CD36 expression is mediated via their interplay with the hypothalamic-pituitary axis, rather than by a direct action on the liver. Thus, the expression of CD36 in hepatocytes is regulated by mechanisms that are distinct from those that regulate fellow class B scavenger receptor family member, SR-BI. In conclusion, CD36 is a known to be a receptor for long chain fatty acids and for both native and modified lipoproteins. If hepatic expression of CD36 is also regulated by steroid sex hormones in humans, these findings could have important implications for understanding differences in lipid handling by the liver in females and males, and the possible consequences of therapeutic manipulation of these hormones.