Biphasic effects of estrogen on apolipoprotein synthesis in human hepatoma cells: mechanism of antagonism by testosterone.
Treatment of HepG2 cells with various concentrations of 17 beta-estradiol has revealed two distinct thresholds for induction of different apolipoproteins. Maximal increases in apolipoprotein AI and CII (apoAI and apoCII) secretion can be obtained with initial concentrations of hormone of 20 nM or greater, while a similar induction of apoB and apoE requires in excess of 500 nM. Both responses involve alterations in the concentrations of apolipoprotein mRNAs. Analyses of the kinetics of accumulation of the apolipoproteins in response to high concentrations of hormone indicate that induction of apoB and apoE occurs coordinately, but it lags behind that of apoAI and apoCII by 5-6 hr. This lag can be eliminated by preexposing the cells to low concentrations of hormone. The ability to induce apoAI and apoCII and the kinetics with which they respond to low levels of estrogen correlate with levels of nuclear type I estrogen binding sites, while increases in apoE and apoB synthesis in response to high concentrations of hormone correlate with the induction of type II sites. Testosterone alone has no effect on the rates of apolipoprotein secretion, but it does increase the concentration of estrogen required to maximally induce apoCII and apoAI by a mechanism that involves high-affinity androgen receptors. This effect may be attributable to the testosterone-dependent induction of a cytoplasmic moderate-affinity estrogen-binding component.
D000818:Animals; D016632:Apolipoprotein A-I; D053302:Apolipoprotein C-I; D001053:Apolipoproteins / Q000096:biosynthesis*; D001054:Apolipoproteins A / Q000096:biosynthesis; D001055:Apolipoproteins B / Q000096:biosynthesis; D001056:Apolipoproteins C / Q000096:biosynthesis; D001057:Apolipoproteins E / Q000096:biosynthesis; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000494:pharmacology*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental; D011960:Receptors, Estrogen / Q000378:metabolism; D013739:Testosterone / Q000494:pharmacology*
D016632:Apolipoprotein A-I; D053302:Apolipoprotein C-I; D001053:Apolipoproteins; D001054:Apolipoproteins A; D001055:Apolipoproteins B; D001056:Apolipoproteins C; D001057:Apolipoproteins E; D011960:Receptors, Estrogen; D013739:Testosterone; D004958:Estradiol