Plasma protein regulation by thyroid hormone

Abstract

Thyroid hormones (THs) regulate growth, development, differentiation and metabolic processes by interacting and activating thyroid hormone receptors (TRs). Although much progress has been made in our understanding of the transcriptional regulation of many TR target genes, little is known of the regulation of plasma protein gene expression by TRs. To investigate the role of TRs in plasma protein expression we used human hepatocellular carcinoma cell lines and carried out cDNA microarray analysis. Our results indicate that several plasma proteins including transferrin, prothrombin, angiotensinogen, haptoglobin, -2-HS-glycoprotein and chain, complement, lipoproteins and fibrinogen are up-regulated by THs. Furthermore, clusterin, -2-macroglobulin precursor, prothymosin and -fetoprotein were found to be down-regulated by THs.Transferrin, an iron-binding protein expressed in all mammals, and mainly synthesized in the liver, was investigated further. Immunoblot and Northern blot analyses revealed that exposure of HepG2-TR 1 sub-lines and HepG2-Neo cells to tri-iodothyronine (T 3 ) induced time-and dose-dependent increases in the abundance of transferrin mRNA and protein, with the extent of these effects correlating with the level of expression of TR 1. Nuclear run-on experiments indicate that this induction is functioning at the transcriptional level. Moreover, cyclohexamide treatment did not eliminate the induction of transferrin by TH. Thus, our results suggest that the induction of transferrin by TH is direct and may in fact be mediated by an as yet unidentified response element in the promoter region.

Stable Isotope Labeling with Amino Acids in Cell Culture (SILAC)-based Quantitative Proteomics Study of a Thyroid Hormone-regulated Secretome in Human Hepatoma Cells

“…These results further confirmed data obtained from SILAC-based analysis, supporting the theory that the SILAC strategy represents a powerful tool to investigate the T 3 -mediated secretome. Furthermore, we identified 25 TH-regulated plasma proteins in the human HCC cell line using cDNA microarray (13). Among them, the current SILACbased secretome mainly contained 21 including transferrin, prothrombin, fibrinogen, angiotensinogen, clusterin, haptoglobin, lipoprotein, and complement.…”

“…Previous microarray analysis experiments by our group have demonstrated that numerous genes including coagulation factor system components (12), plasma proteins (12,13), nuclear receptor coactivator (14), antimetastatic proteins (15), proteases (16), and oncogenes (17) are regulated by T 3 . Additionally, we have identified several T 3 -regulated extracellular proteins such as matrix metalloproteinases (MMPs) and cysteine cathepsins.…”

α2-Heremans-Schmid Glycoprotein/ Fetuin-A Is Associated With Insulin Resistance and Fat Accumulation in the Liver in Humans

“…Recombinant human interleukin-6, interleukin-1␤ (20), and tumor necrosis factor-␣ and partial hepatectomy (21) were found to downregulate the synthesis of Ahsg. In contrast, AHSG mRNA expression was upregulated upon treatment of hepatocellular carcinoma cells with thyroid hormones (22) and after overexpression of signal transducer and activator of transcription-3 (23). The mechanisms by which liver fat induces AHSG production are unknown and require clarification.…”

Hormetic responses of thyroid hormone calorigenesis in the liver: Association with oxidative stress

“…In addition to TNF-a/IKK/NF-jB pathway (69-71), T 3 induced the Kupffer-cell-dependent release of IL-6, and activation of hepatic STAT3 may control both type I (haptoglobin) and type II (bfibrinogen) APP genes (67). Thyroid hormones also activate transcriptionally the hepatic synthesis of the APPs a 1 -acid glycoprotein, a 2 -(acute phase) globulin (72), ceruloplasmin (73), angiotensinogen, complement component 4A, and serum amyloid A protein precursor (74), as well as that of ferritin posttranscriptionally (75). The latter acute-phase response (APR) of the liver is a major pathophysiologic reaction in which normal homeostatic mechanisms are replaced by new set points contributing to defensive or adaptive capabilities against inflammation and oxidative stress (76).…”