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

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 downregulated 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 LDLreceptor 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 cholesterollowering effect of ACTH in vivo may be a decreased production rate of apoB-containing lipoproteins from the liver. 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). ACTH has also been shown to influence plasma lipid and lipoprotein metabolism (2-7). Thus, we have demonstrated previously that ACTH treatment markedly and consistently lowers plasma concentrations of low density lipoproteins (LDL), very low density lipoprotein (VLDL), and lipoprotein(a) (Lp(a)) in healthy individuals (2, 7), in steroid-treated patients with renal disease, and in uremic patients treated by hemodialysis (3, 4). In some of the studies, an increased high density lipoprotein (HDL) cholesterol concentration was also observed (4, 6). The effects of ACTH on LDL and Lp(a) levels seem attributable to ACTH as such, because they are clearly distinct from the effects of equipotent doses of corticosteroids (6).The mechanisms behind the lipid-lowering effects of ACTH are not known. Previous data indicated that ACTH could increase LDL receptor (LDL-R) activity in HepG2 cells (6), suggesting that an increased elimination rate of LDL might be involved. It has also been reported that ACTH increased the receptor-mediated uptake of native LDL but not of oxidized LDL or of LP(a) in HepG2 cells. However, 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) concentrati...

ACTH reduces the rise in ApoB-48 levels after fat intake

“…Thus, our results are consistent with the hypothesis that ACTH administration is associated with a reduced output of chylomicrons after a fat meal. This interpretation is in line with our previous in vitro study, where decreased intracellular levels of ApoB mRNA and decreased secretion of ApoB was seen in liver cells after exposure to ACTH in vitro (8). Taken together, these observations are consistent with the view that impaired synthesis of ApoB is also involved in the lipidlowering action of ACTH in man in vivo.…”

“…This study further confirms earlier reports on the lipid-lowering effects of ACTH and supports our theory, based on in vitro data, that the lipid lowering effects of ACTH administration in man involves an inhibition of the synthesis of ApoB (8). Thus, the action of ACTH would be at least in part attributed to a reduced production and secretion of apoB-containing lipoproteins.…”

“…Taken together, these observations are consistent with the view that impaired synthesis of ApoB is also involved in the lipidlowering action of ACTH in man in vivo. The present study does not allow conclusions as to the detailed biological mechanisms; although modulation of ApoB gene transcript is probable, as previously demonstrated in HepG2 cells (8), presecretory degradation of ApoB, a wellestablished regulatory mechanism, is also possible. Further studies using human intestinal (Caco2) and hepatic (HepG2) cell lines may be useful tools to further delineate the inhibitory mechanisms of ACTH on ApoB synthesis.…”

“…To test the hypothesis that decreased synthesis of ApoB, as observed in vitro (8), is involved in the reduction of ApoB-containing lipoproteins in response to ACTH in vivo, this study was designed to monitor the effects of ACTH on plasma concentrations of ApoB-containing lipoproteins, which rapidly increase after fat intake. This postprandial lipidemia is mainly accounted for by intestinal production of chylomicrons, which contain ApoB-48.…”

“…There is support for both alternatives. Although ACTH does not seem to modulate the activity or expression of the LDL receptor or scavenger receptor-BI (8) there is evidence that increased removal rate may be one mechanism of action. Thus, we have suggested, from observations in clinical studies, that ACTH may act by enrichment of VLDL and LDL with apoE (4,7).…”