Abstract
Our previous study found that thyroid-stimulating hormone promoted sterol regulatory element-binding protein-2 (SREBP-2) expression and suppressed AMP-activated protein kinase (AMPK) activity in the liver, but it was unclear whether there was a direct link between TSH, AMPK and SREBP-2. Here, we demonstrate that the 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR)-induced activation of AMPK directly inhibited the expression of SREBP-2 and its target genes HMGCR and HMGCS, which are key enzymes in cholesterol biosynthesis, and suppressed the TSH-stimulated up-regulation of SREBP-2 in HepG2 cells; similar results were obtained in TSH receptor knockout mice. Furthermore, AMPK, an evolutionally conserved serine/threonine kinase, phosphorylated threonine residues in the precursor and nuclear forms of SREBP-2, and TSH interacted with AMPK to influence SREBP-2 phosphorylation. These findings may represent a molecular mechanism by which AMPK ameliorates the hepatic steatosis and hypercholesterolemia associated with high TSH levels in patients with subclinical hypothyroidism (SCH).
Highlights
Thyroid-stimulating hormone is secreted by the pituitary and regulates thyroid growth and differentiation
We demonstrate that the 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR)-induced activation of AMPK directly inhibited the expression of sterol regulatory element-binding protein-2 (SREBP-2) and its target genes hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and hydroxy-3-methylglutaryl-CoA synthase (HMGCS), which are key enzymes in cholesterol biosynthesis, and suppressed the TSH-stimulated up-regulation of SREBP-2 in HepG2 cells; similar results were obtained in TSH receptor knockout mice
Subclinical hypothyroidism (SCH), which is characterized by normal thyroid hormone levels and elevated TSH levels, is often accompanied by hypercholesterolemia and associated with cardiovascular disease [7]
Summary
Thyroid-stimulating hormone is secreted by the pituitary and regulates thyroid growth and differentiation. Recent studies have discovered that TSH is a tropic hormone that has multiple effects on metabolism, including cholesterol synthesis and glucose metabolism [1, 2]. Several epidemiological studies have indicated positive correlations between TSH and total cholesterol, triglycerides, and low-density lipoprotein cholesterol (LDL-c) [3,4,5,6]. Subclinical hypothyroidism (SCH), which is characterized by normal thyroid hormone levels and elevated TSH levels, is often accompanied by hypercholesterolemia and associated with cardiovascular disease [7]. More studies are focusing on the relationship between TSH and hypercholesterolemia to explore novel approaches for preventing cardiovascular disease.
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