The role of receptor-mediated low-density lipoprotein uptake and degradation in the regulation of progesterone biosynthesis and cholesterol metabolism by human trophoblasts.
Dispersed human placental trophoblastic cells, maintained in primary culture, utilize principally cholesterol derived from low-density lipoprotein (LDL) for progesterone biosynthesis. The rate of secretion of progesterone by these cells increased (100 ng X mg-1 cell protein X 24 h-1 to 390 ng X mg-1 cell protein X 24 h-1) as the LDL concentration in the culture medium was increased (0 to 420 micrograms protein X ml-1). At an HDL-protein concentration of 1000 micrograms protein X ml-1, the rate of progesterone secretion by these cells was one-half that attained by cells maintained in medium containing LDL. The uptake of [125I]iodo-LDL by trophoblastic cells increased at [125I]iodo-LDL concentrations between 0 and 14 micrograms protein X ml-1 in the culture medium, was maximal by 5 to 6 h, and was diminished progressively as the concentration of non-radiolabelled LDL, but not HDL, was increased. Degradation of [125I]iodo-LDL increased as a function of the [125I]iodo-LDL concentration in the culture medium, was linear from 30 min to 32 h, was inhibited by the addition of choloroquine (40 mumol/1) to the culture medium; and was diminished progressively as the concentration of non-radiolabelled LDL, but not HDL, was increased. We observed a reduction in uptake and degradation of [125I]iodo-LDL by these cells as a function of the LDL concentration in the preincubation culture medium. Moreover, when the cells were preincubated with LDL for various times, a 90 per cent reduction in the rate of uptake and degradation of [125I]iodo-LDL was observed after 14 h. These findings are suggestive that trophoblastic cells are capable of down-regulating the number of LDL receptors on the cell surface. The incorporation of radiolabelled oleic acid into cholesteryl esters by these cells was linear for 6 h, increased as a function of the oleic acid concentration in the culture medium, and was stimulated when LDL was present in the culture medium. On the other hand, the synthesis of cholesteryl esters was inhibited half-maximally when the progesterone concentration in the culture medium was 20 mumol/1. Finally, the incorporation of [14C]acetate into cholesterol was inhibited as a function of the LDL concentration in the culture medium. Based on the results of these studies, our belief is that mechanism(s) have been elucidated to define the regulation of (1) progesterone biosynthesis; (2) de novo cholesterol synthesis; (3) intracellular cholesteryl ester storage; and (4) LDL uptake by normal human trophoblastic cells.
D002784:Cholesterol / Q000378:metabolism*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008077:Lipoproteins, LDL / Q000378:metabolism* / Q000494:pharmacology; D011247:Pregnancy; D011374:Progesterone / Q000096:biosynthesis*; D011956:Receptors, Cell Surface / Q000032:analysis / Q000502:physiology*; D011973:Receptors, LDL; D002785:Sterol O-Acyltransferase / Q000032:analysis; D014327:Trophoblasts / Q000378:metabolism*
D008077:Lipoproteins, LDL; D011956:Receptors, Cell Surface; D011973:Receptors, LDL; D011374:Progesterone; D002784:Cholesterol; D002785:Sterol O-Acyltransferase