ACTH Decreases the Expression and Secretion of Apolipoprotein B in HepG2 Cell Cultures

Ning Xu,Ulf Ekstrom,Peter Nilsson-Ehle

doi:10.1074/jbc.m104659200

Abstract

Administration of adrenocorticotropic hormone (ACTH) has been shown to decrease plasma concentrations of apolipoprotein B (apoB) containing lipoproteins, including lipoprotein(a), in man. However, the mechanism behind this hypolipidemic effect is unknown. This study aimed at distinguishing between the main possibilities (increased elimination or decreased production of lipoproteins) using HepG2 cell cultures. Addition of ACTH to the cell culture medium selectively down-regulated apoB mRNA expression and apoB secretion in a dose-dependent manner. At 100 pmol/liter ACTH, the apoB mRNA level was about 40% lower than in the untreated cells, and the secretion of apoB into the medium was decreased to a similar extent. The expression and secretion of other apolipoproteins (apoA-I, apoE, and apoM), however, were not affected by ACTH. Under normal culture conditions the level of secretion of apoB from HepG2 cells is quite low. In the presence of 0.4 mmol/liter oleic acid secretion of apoB increased 3-fold, but this phenomenon was not seen in ACTH-treated cells. Binding and internalization of radiolabeled low density lipoprotein (LDL) by HepG2 cell, as well as LDL-receptor mRNA and scavenger receptor B-I mRNA levels, were not influenced by ACTH. In conclusion, ACTH directly and selectively down-regulated the production and secretion of apoB in HepG2 cell cultures, suggesting that a principal mechanism behind the cholesterol-lowering effect of ACTH in vivo may be a decreased production rate of apoB-containing lipoproteins from the liver.

Highlights

It is well documented that adrenocorticotropic hormone (ACTH)1 regulates important aspects of lipid metabolism in the adrenal gland, especially those related to steroid hormone homeostasis (1)
We investigated the effects of ACTH on the expression and secretion of apolipoprotein B (apoB) and other apolipoproteins and re-examined the influence of ACTH on the receptor-mediated uptake of low density lipoprotein (LDL) in HepG2 cell cultures
Effect of ACTH on the Secretion of Apolipoproteins from HepG2 Cells—Fig. 1 demonstrates the contents of apoB in the medium from cell cultures exposed to ACTH for 6, 12, and 24 h, respectively

Summary

Introduction

It is well documented that adrenocorticotropic hormone (ACTH) regulates important aspects of lipid metabolism in the adrenal gland, especially those related to steroid hormone homeostasis (1). ACTH has been shown to influence plasma lipid and lipoprotein metabolism (2–7). It has been reported that ACTH increased the receptor-mediated uptake of native LDL but not of oxidized LDL or of LP(a) in HepG2 cells. Because the elimination of LDL and Lp(a) from the circulation occurs via distinctly different routes (i.e. Lp(a) does not utilize the LDL-R pathway), the parallel decrease in plasma LDL and Lp(a) concentrations after administration of ACTH in vivo indicates that other mechanisms must be involved. We investigated the effects of ACTH on the expression and secretion of apoB and other apolipoproteins and re-examined the influence of ACTH on the receptor-mediated uptake of LDL in HepG2 cell cultures. Because LDL removal may occur by the LDL-R and by the scavenger receptor BI (SR-BI) (9, 10), we monitored the effects of ACTH on the expression of these two receptors

Objectives

Results

Conclusion