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Endocrine and cellular physiology and pathology of the insulin-like growth factor acid-labile subunit

Nature Reviews Endocrinology (2024)Cite this article

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Abstract

The acid-labile subunit (ALS) of the insulin-like growth factor (IGF) binding protein (IGFBP) complex, encoded in humans by IGFALS, has a vital role in regulating the endocrine transport and bioavailability of IGF-1 and IGF-2. Accordingly, ALS has a considerable influence on postnatal growth and metabolism. ALS is a leucine-rich glycoprotein that forms high-affinity ternary complexes with IGFBP-3 or IGFBP-5 when they are occupied by either IGF-1 or IGF-2. These complexes constitute a stable reservoir of circulating IGFs, blocking the potentially hypoglycaemic activity of unbound IGFs. ALS is primarily synthesized by hepatocytes and its expression is lower in non-hepatic tissues. ALS synthesis is strongly induced by growth hormone and suppressed by IL-1β, thus potentially serving as a marker of growth hormone secretion and/or activity and of inflammation. IGFALS mutations in humans and Igfals deletion in mice cause modest growth retardation and pubertal delay, accompanied by decreased osteogenesis and enhanced adipogenesis. In hepatocellular carcinoma, IGFALS is described as a tumour suppressor; however, its contribution to other cancers is not well delineated. This Review addresses the endocrine physiology and pathology of ALS, discusses the latest cell and proteomic studies that suggest emerging cellular roles for ALS and outlines its involvement in other disease states.

Key points

  • The insulin-like growth factor (IGF) acid-labile subunit (ALS), encoded by IGFALS, forms a circulating ternary complex with IGF binding protein (IGFBP)-3 or IGFBP-5, and IGF-1 or IGF-2.

  • This ternary complex acts as a reservoir of IGF-1 and IGF-2 in the bloodstream and has a central role in regulating their endocrine transport and tissue bioavailability.

  • Owing to the induction of its expression by growth hormone and suppression by IL-1β, ALS might serve as a marker of growth hormone secretion and/or activity and of inflammation.

  • Mutation, deletion or inactivation of the gene that encodes ALS in humans and mice decreases circulating levels of IGF-1 and IGFBP-3, causing moderate growth deficiency and abnormalities in bone and carbohydrate metabolism.

  • As a marker of inflammation and sepsis, ALS levels are low in critical illness, cardiovascular disease and COVID-19; in some conditions, ALS levels might predict disease progression and mortality.

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Fig. 1: Structure of the acid-labile subunit.
Fig. 2: Complex formation by the acid-labile subunit.
Fig. 3: The acid-labile subunit and ageing.
Fig. 4: Regulation of acid-labile subunit synthesis.

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    Robert C. Baxter

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Baxter, R.C. Endocrine and cellular physiology and pathology of the insulin-like growth factor acid-labile subunit. Nat Rev Endocrinol (2024). https://doi.org/10.1038/s41574-024-00970-4

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