Abstract
Even though the liver synthesizes most of circulating IGF-1, it lacks its receptor under physiological conditions. However, according to previous studies, a damaged liver expresses the receptor. For this reason, herein, we examine hepatic histology and expression of genes encoding proteins of the cytoskeleton, extracellular matrix, and cell-cell molecules and inflammation-related proteins. A partial IGF-1 deficiency murine model was used to investigate IGF-1’s effects on liver by comparing wild-type controls, heterozygous igf1+/−, and heterozygous mice treated with IGF-1 for 10 days. Histology, microarray for mRNA gene expression, RT-qPCR, and lipid peroxidation were assessed. Microarray analyses revealed significant underexpression of igf1 in heterozygous mice compared to control mice, restoring normal liver expression after treatment, which then normalized its circulating levels. IGF-1 receptor mRNA was overexpressed in Hz mice liver, while treated mice displayed a similar expression to that of the controls. Heterozygous mice showed overexpression of several genes encoding proteins related to inflammatory and acute-phase proteins and underexpression or overexpression of genes which coded for extracellular matrix, cytoskeleton, and cell junction components. Histology revealed an altered hepatic architecture. In addition, liver oxidative damage was found increased in the heterozygous group. The mere IGF-1 partial deficiency is associated with relevant alterations of the hepatic architecture and expression of genes involved in cytoskeleton, hepatocyte polarity, cell junctions, and extracellular matrix proteins. Moreover, it induces hepatic expression of the IGF-1 receptor and elevated acute-phase and inflammation mediators, which all resulted in liver oxidative damage.
Highlights
The liver is the main source of circulating insulin-like growth factor-1 (IGF-1)
The heterozygous mice (Hz) + IGF-1 group showed an increase of IGF-1 levels as compared to the Hz group (681.3 ± 7.7 ng/mL, p < 0.01), reaching similar values when compared to controls (WT)
WT a treatment was able to bring up the weight to normal values as no difference was observed among treated Hz animals as compared to controls (Hz + IGF-1, 39.6 ± 0.8 g, vs. WT not significant; vs. Hz p < 0.01)
Summary
The liver is the main source of circulating insulin-like growth factor-1 (IGF-1) (more than 75%). It is produced following growth hormone (GH) endocrine stimulus. The liver is not a target organ for this hormone as liver cells do not express the receptor under physiological conditions. Since IGF-1 has a wide range of physiological roles, its activity must be strictly controlled, where IGFBPs play their part. These binding proteins help to modulate the interaction between IGF-1 and its receptor (IGF-1R), thereby indirectly controlling IGF-1 biological activity [15]. IGFBPs possess IGF-1-independent actions mediated by their own membrane or intracellular receptors [15]
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