Regulation of the acid-labile subunit in sustained endotoxemia

Abstract

The effect of sustained endotoxemia on expression of the acid-labile subunit (ALS) in relation to hepatic markers of altered GH and insulin sensitivity was examined. Juvenile rats were injected with endotoxin twice daily for 48 h, causing reduced food intake and attenuated growth. In pair-fed controls, food restriction caused marked suppression of ALS gene expression and circulating levels within 12 h, and endotoxemia augmented this effect. This acute effect of endotoxin corresponded temporally with transient induction of suppressor of cytokine signaling (SOCS)-3, cytokine-inducible SH2-containing protein (CIS), phosphoenolpyruvate carboxykinase (PEPCK), and insulin-like growth factor-binding protein (IGFBP)-1 and suppression of GH receptor (GHR). During the subsequent 36 h of sustained endotoxin treatment, expression of ALS recovered to, and then rose above, that of their pair-fed controls. This effect was paralleled by other ternary complex components. The inductive effect of sustained endotoxemia relative to pair-fed controls could not be explained by differences in expression of GHR, SOCS-3, or CIS but coincided with normalized PEPCK and IGFBP-1 levels, suggesting better hepatic insulin sensitivity in these animals. These data may indicate that, in sustained endotoxemia, ALS levels are regulated through modulation of hepatic insulin sensitivity. insulin sensitivity; insulin-like growth factor-binding protein-5; ternary complexes; liver THE ACID-LABILE SUBUNIT (ALS) of the 150-kDa insulinlike growth factor-binding protein (IGFBP) complex is an 85-kDa glycoprotein that is thought to regulate the bioavailability of IGFs in the serum, and possibly other tissue compartments, by sequestering them in a ternary complex with either IGFBP-3 or 6,13,22,48). Prolonged critical illness is characterized by severe wasting of lean body mass that has been attributed partly to suppression of the IGF axis (3,5,47,50). Concordantly, serum levels of ALS and other ternary complex components have been found to be decreased in critically ill patients (2,5,11,49).Circulating levels of ALS have been found to correlate strongly with IGFBP-3 and IGFBP-5 serum concentrations (7) and consequently would be expected to affect the bioavailability and metabolic activity of the IGFs in serum. ALS and IGF-I are expressed predominantly in the liver, and their expression is regulated at the level of transcription by GH (12,23,39). Additionally, we have found that insulin modulates hepatic expression of ALS (17, 18). Altered hepatic sensitivity to GH and insulin would be expected to modulate circulating levels of ALS and, consequently, other components of the ternary complexes.The effects of sustained endotoxemia on ALS expression have not yet been studied. Sustained endotoxemia in rats provides a model of inflammation-induced catabolism different from endotoxemic shock and very acute responses measured within hours of administration of a potentially lethal dose of lipopolysaccharide. We have used the model of sustained endotoxemia described by P...

Endotoxin at low doses stimulates pituitary GH whereas it decreases IGF-I and IGF-binding protein-3 in rats

“…This hypothesis is consistent with the data showing that IGF-I/IGFBP-3 binary complex administration to septic rats restores gastrocnemius protein synthesis to a rate comparable with that of control rats (Svanberg et al 2000), suggesting that the binary complex administration accelerates protein synthesis by prolonging the availability of IGF-I. The binary complexes form a ternary complex with the acid-labile subunit (ALS), and endotoxin administration also induces a decrease in serum concentrations of ALS (Barreca et al 1998, Kong et al 2002. Then, the decrease in circulating IGFBP-3 and ALS might contribute to the decline in serum IGF-I observed after LPS administration.…”

Growth Hormone Signaling in the Regulation of Acid Labile Subunit

“…Recent studies show that in human cirrhosis, levels of ALS, IGF-I and GHR mRNA are significantly decreased (Moller et al, 2000;Donaghy et al, 2002). Similar observations have been reported in liver of LPS treated rats (Kong et al, 2002b). These catabolic conditions also increase the secretion of glucocorticoid and production of cellular cAMP (Frystyk et al, 1998;Moller et al, 2000), two factors shown to reduce ALS secretion in primary hepatocytes Delhanty and Baxter, 1998).…”

“…Disease and catabolic state : Several studies demonstrate that ALS production is reduced during catabolic conditions Oster et al, 1995;Bereket et al, 1996;Lang et al, 1996;Frystyk et al, 1999;Fukuda et al, 1999;Moller et al, 2000;Kong et al, 2002a;Kong et al, 2002b). In humans, suffering from burn injury or cirrhosis, ALS synthesis is decreased (Frystyk et al, 1998;Moller et al, 2000).…”

Inactivation of Kupffer cells by gadolinium administration prevents lipopolysaccharide-induced decrease in liver insulin-like growth factor-I and IGF-binding protein-3 gene expression

“…IGFBP-3 is the major IGFBP in serum; the decrease in serum concentrations of IGFBP-3 may contribute to increasing IGF-I turnover and then to reducing IGF-I half-life in serum. The binary complexes form a ternary complexes with the acid-labile subunit, or ALS, and endotoxin administration also induces a decrease in serum concentrations of ALS (Barreca et al 1998, Kong et al 2002. Then the decrease in circulating IGFBP-3 and ALS might contribute to the decline in serum IGF-I observed after LPS administration.…”