The inhibition of low density lipoprotein metabolism by transforming growth factor-beta mediates its effects on steroidogenesis in bovine adrenocortical cells in vitro.
Transforming growth factor-beta (TGF beta) has a differential effect on the growth and function of bovine adrenocortical cells in vitro. TGF beta inhibits basal as well as ACTH- or angiotensin II-stimulated steroid formation, with no evidence of change in cell growth. The major inhibitory effect of TGF beta occurs at a step before cholesterol formation, since treatment of adrenocortical cells with TGF beta decreased not only delta 4-steroid levels but also delta 5-steroid levels. The addition of cholesterol reverses the suppression of steroidogenesis induced by TGF beta. To determine the mechanism of this inhibition, the effect of TGF beta on low density lipoprotein (LDL) metabolism was investigated. Cells treated with TGF beta showed a significant suppression of [125I]iodohuman LDL ([125I]LDL) binding to the cell surface, followed by decreases in internalization and proteolytic degradation of [125I]LDL. Maximal inhibition of LDL metabolism was observed at a concentration of 1 ng/ml (4 X 10(-11) M) TGF beta. The stimulation of LDL metabolism by ACTH was also inhibited by TGF beta, and the inhibition observed correlated well with the inhibition of steroidogenesis. The inhibitory effect of TGF beta on [125I]LDL binding results from the decrease in the maximal LDL-binding capacity. The stimulation of LDL uptake induced by Bu2cAMP, cholera toxin, forskolin, and Ang II was also decreased by treatment with 1 ng/ml TGF beta. The specificity of this effect is quite high, since the inhibitory effects of TGF beta on LDL metabolism were not observed with either inhibin A or activin, two molecules that have considerable structural homology to TGF beta. We conclude that TGF beta specifically suppresses LDL metabolism in bovine adrenocortical cell cultures and that this step may mediate, at least in part, its role as a potent inhibitor of steroidogenesis.
D000302:Adrenal Cortex / Q000187:drug effects / Q000378:metabolism*; D000305:Adrenal Cortex Hormones / Q000096:biosynthesis*; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000818:Animals; D002417:Cattle; D006133:Growth Substances; D006854:Hydrocortisone / Q000096:biosynthesis; D006888:Hydroxycholesterols / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology*; D011973:Receptors, LDL / Q000187:drug effects / Q000502:physiology; D015291:Transforming Growth Factors
D000305:Adrenal Cortex Hormones; D006133:Growth Substances; D006888:Hydroxycholesterols; D008077:Lipoproteins, LDL; D010455:Peptides; D011973:Receptors, LDL; D015291:Transforming Growth Factors; C007997:25-hydroxycholesterol; D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone