CONTINUOUS BUT NOT INTERMITTENT ADMINISTRATION OF GROWTH-HORMONE TO HYPOPHYSECTOMIZED RATS INCREASES APOLIPOPROTEIN-E SECRETION FROM CULTURED-HEPATOCYTES

Hypophysectomy of female rats has been shown to decrease the serum lev els of apolipoprotein E (apoE). Continuous but not intermittent admini stration of GH to hypophysectomized (HX) rats increases these levels t o those of normal rats, indicating that the sexually dimorphic secreti on of GH is important in the regulation of apoE metabolism. In this st udy, these effects of GH were further investigated by studying the bio synthesis and secretion of apoE from isolated hepatocytes. Hepatocytes were isolated from HX rats as well as from HX rats that had received hormonal treatment with T-4 and cortisol (C) or T-4 and C together wit h GH given either as two daily sc injections (GHx2) or as a continuous infusion (GHc). Hypophysectomy decreased by 47% the amount of apoE pr esent in the culture medium after a 4-h incubation. Treatment of HX ra ts with Te and C alone or in combination with GHx2 did not influence t he amount apoE present in the medium, whereas treatment with T-4, C, a nd GHc increased the amount of apoE to that of normal controls. The di fferent levels of apoE in the medium was not due to differences in the disappearance of apoE, indicating that it was caused by changes in th e rate of apoE secretion. Consistent with this, hypophysectomy decreas ed the rate of intracellular accumulation of apoE measured by incubati on of the cells with [S-35]methionine for 0, 8, and 20 min. Treatment with T-4, C, and GHc increased the rate of accumulation, but T-4, C, a nd GHx2 had no effect. The differences in the initial rate of intracel lular accumulation of apoE were not due to variations in apoE messenge r RNA pools or to differences in the degradation of apoE at a step ear ly in the secretory pathway. These results indicate that the differenc es in the initial rate of accumulation of apoE results from difference s in the translational rate. The major amount of apoE that was secrete d to the medium appeared in the high-density lipoprotein fraction, whe reas small amounts were present in the very-low-density lipoprotein fr action (VLDL). Hypophysectomy decreased the amount of newly secreted a poE in the VLDL fraction. Only therapy with T-4, C, and GHc could rest ore the normal distribution of apoE in the VLDL fraction. In conclusio n, the results indicate that the secretory pattern of GH is involved i n the regulation of the apoE secretion by influencing the rate of tran slation.