Impaired Insulin‐like Growth Factor‐1 function in X‐linked Adrenoleukodystrophy patients

Abstract

IntroductionX‐linked Adrenoleukodystrophy (X‐ALD), a common peroxisomal disorder is characterized by elevated very long chain fatty acids (VLCFA) levels in tissues and body fluids of patients. X‐ALD patients present with adrenal insufficiency, demyelination and progressive mental retardation and IGF‐1 has been reported to alleviate demyelination and neurodegeneration in an animal model of X‐ALD. We examined the effect of VLCFA on IGF‐1 function in human skin fibroblasts.MethodsHuman skin fibroblasts grown from skin explants were cultured in growth medium. Cell cultures were treated with varying concentrations of IGF‐1 and/or VLCFA (Lignoceric acid; C24:0, hexadecanoic acid; C26:0 ) for 24–72 hrs. DNA synthesis into cultured fibroblasts was measured and total RNA was extracted for RT‐PCR analysis of IGF‐1 receptor and GAPDH. Cell homogenates were prepared for western blotting and protein measurements. Levels of IGF‐1 and VLCFA were measured in blood samples of 10 patients with confirmed diagnosis of X‐ALD.ResultsBoth VLCFAs used in this study significantly (p <0.01) reduced the IGF‐1–induced DNA synthesis in cultured skin fibroblasts. Lignoceric acid as well as hexadecanoic acid markedly reduced the gene expression of IGF‐1 receptor. IGF‐1 receptor protein was also significantly reduced following 48 hrs of treatment with VLCFAs. X‐ALD patients were observed to have significantly lower levels of plasma IGF‐1 as compared to healthy controls.ConclusionsThis study suggests that abnormally elevated VLCFA in X‐ALD patients might impair IGF‐1 function through downregulation of IGF‐1 receptor thereby providing a new insight into molecular mechanisms of X‐ALD pathogenesis.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.