Regulation of the acid-labile subunit of the 150-kDa IGF-binding protein complex and its role in the circulating IGF system¹

ABSTRACT In postnatal animals, most of the IGF-I and IGF-II circulates in ternary complexes of 150 kDa composed of one molecule each of IGF-I or IGF-II, IGF binding protein-3 or -5, and an acid-labile subunit (ALS). Circulation of IGF-I and IGF-II in 150-kDa complexes leads to their retention in the vascular system and promotes their endocrine actions. This review focuses on recent progress on the biology of ALS, the most important factor driving the formation of the150-kDa complex in plasma. In a variety of animals, including sheep, the single-copy ALS gene spans approximately 3.3 kb and is composed of two exons and one intron. Transcription of the ALS gene produces a mRNA of about 2.2 kb, which encodes proteins of 603 amino acids in mice and 611 amino acids in sheep. Mature ALS circulates in plasma as a glycosylated protein of 84 to 86 kDa and is organized by repeating leucine-rich domains of 24 amino acids into a donut-shaped protein. In all species studied so far, the ALS gene is expressed at high levels only in liver. In sheep, weak expression is first detected at d 130 of fetal life, increases suddenly during the 1st wk after birth, and changes little thereafter. After birth, growth hormone increases ALS synthesis by activating transcription of the gene. Analysis of sheep, mouse, and human ALS promoters reveals conservation of a growth hormone response element. This element mediates the effects of growth hormone by binding signal transducer and activator of transcription-5a and -5b, two related transcription factors. To define the role of ALS in the circulating IGF system, studies have been performed in ALS-null mice, which are devoid of both ALS and 150-kDa complexes. ALS null mice grow at a slower rate after birth than wild-type mice. This growth depression is associated with 65 to 90% decreases in the plasma concentrations of IGF-I and IGF binding protein-3, indicating that ALS is needed to maintain plasma concentrations of both proteins. In conclusion, ALS plays a critical role in regulating the plasma concentration of IGF-I and IGF-II and their access to target tissues. In view of this important role, ALS must be considered in future studies if animal scientists are to understand the roles of plasma IGF-I and -II in regulating important productive functions such as growth, reproduction, and lactation.

Implications

Plasma insulin-like growth factor-I and -II play critical roles in the regulation of productive functions such as reproduction, growth, and lactation. However, we still have an incomplete understanding of factors regulating their concentrations and their access to target tissues. One factor known to regulate both of these processes is the acid-labile subunit. Despite this important role, the acid-labile subunit has generally not been considered when studying changes in plasma insulin-like growth factors that occur in domestic animals during development, nutrition, and physiological states. This omission must be corrected before animal scientists can understand and take advantage of the insulin-like growth factor system to improve efficiency of productive functions.

Key Words: Insulin-like Growth Factor, Endocrinology, Liver, Somatotropin, Transcription

© 2001, by the American Society of Animal Science. All rights reserved.

J. Anim. Sci. 2001. 79:E41-E47