Effects of estradiol on the endocytic transport of vitamin D carrier protein in hepatocytes.

BACKGROUND:The possible modulation of receptor-mediated endocytosis (RME) by sex steroids is not well understood, especially in terms of the different receptor-ligand systems and cell types that may exhibit such regulation. The main objective of the current study was to examine the short-term effects of 17β-estradiol (E2) on RME of an extracellular carrier protein for calciferols, vitamin D-binding protein (DBP). METHODS:Murine male and female primary hepatocytes were treated for 30min in the absence (controls) or presence of Ε2 (1μM). Labeled DBP was then added, and its endocytosis was measured after an incubation of 10min at 37°C using standard ELISA techniques. To obtain further insight into potential molecular mechanisms, fulvestrant and 17α-ethinyl estradiol (EE) were also analyzed. And as part of comparative analyses, a second nutrient carrier protein, vitamin A-binding protein (RBP), was also analyzed. RESULTS:The results provide the first evidence for an estradiol-dependent stimulation of DBP endocytosis (p<0.05 relative to controls without Ε2). This stimulation, however, was only observed in female hepatocytes. Uptake of RBP was enhanced to a similar extent as DBP by estradiol. In normal (non-estradiol treated) male and female hepatocytes such changes in DBP or RBP endocytosis were not observed. Both fulvestrant and EE exhibited a significant (p<0.05), but incomplete, inhibition of Ε2-dependent stimulation of endocytosis. CONCLUSIONS:The results provide novel evidence for Ε2 effects on endocytic transport; and for gender-related differences in E2-enhanced transport. These Ε2 effects may be partly dependent on estrogen receptors; but possible, additional or alternative mechanisms are also proposed. GENERAL SIGNIFICANCE:Endocytic transport is a fundamental function whose regulation has implications for cell signaling, growth, survival, differentiation, and death. This study helps delineate a possible endocrine regulatory pathway involving modulation of endocytosis by a steroid hormone. It also provides a potential, new relation between different hormonal regulators, e.g., estradiol effects on cellular assimilation of calciferols.

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