Elsevier

Metabolism

Volume 44, Issue 6, June 1995, Pages 730-738
Metabolism

Glucocorticoids upregulate high-affinity, high-density lipoprotein binding sites in rat hepatocytes

https://doi.org/10.1016/0026-0495(95)90185-XGet rights and content

Abstract

Glucocorticoid hormones (GL) regulate high-density lipoprotein (HDL) plasma concentrations by increasing synthesis and secretion of HDL by the liver. However, little is known about the effect of GL on the uptake and processing of HDL by hepatocytes (HEP). To investigate this question, we studied the effects of dexamethasone (DEX) on the expression of high-affinity HDL-binding sites via the specific binding and internalization of iodine-labeled apolipoprotein E (apo E)-free HDL3 in a culture of rat HEP. Specific binding and internalization of HDL3 decreased by 60% in cells cultured in the absence of DEX for 48 hours. At concentrations of 10−7 and 10−5 mol/L, DEX prevented the decrease, maintaining specific binding and internalization versus the control level (at 24 hours). HDL-binding sites with a Kd of 20 μg/mL were revealed on the surface of cultured HEP. HEP demonstrated a greater binding capacity in the presence of DEX at concentrations of 10−7 and 10−5 mol/L (125 v 45 ng/mg cell protein). The effect of the hormone has demonstrated to be dose-dependent at concentrations between 10−9 and 10−7 mol/L, leveling off at 10−7. Higher concentrations did not induce a further increase in specific binding and internalization. Withdrawal of the hormone from culture medium was associated with a decrease in specific binding of the ligand by 60% in the following 24 hours. To investigate the effect of glucocorticoid deficiency on liver uptake of HDL in vivo, specific binding and internalization were studied in a culture of HEP isolated from adrenalectomized rats (AER) at 2 hours after seeding. The HEP demonstrated a 2.5-fold decrease in specific binding versus those from normal rats (NR). Correction of the glucocorticoid deficiency in AER by intramuscular injection of DEX at a dose of 5 μg per rat restored the specific binding of HDL3 at 2 hours after seeding. Replacement of the hormone by incubation of HEP from AER with DEX increased specific binding and internalization of the ligand in a dose-dependent fashion until NR levels were attained. In both cases, the upregulating effect of DEX was stopped by 0.5 mmol/L cycloheximide. Lovastatin (100 nmol/L) blocked the DEX-dependent increase in cholesterol synthesis, but failed to prevent the DEX-induced increase in specific binding and internalization of 125I-HDL3. It is concluded that the specific binding and internalization of 125I-HDL3 by liver parenchymal cells are reversibly regulated by physiologic and pharmacologic concentrations of DEX. Its effect does not depend on availability of the pool of newly synthesized cholesterol, but it seems to be a result of the increase in the synthesis of HDL-binding protein.

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    Supported by the Academy of Medical Science, Russia.

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