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Updated: Aug 17, 2026
In vivo Characterization of Endocrine Disrupting Chemical Effects via Thyroid Hormone Action Indicator Mouse
Published on: October 6, 2023
Selective thyroid receptor modulation by GC-1 reduces serum lipids and stimulates steps of reverse cholesterol
Lisen Johansson1, Mats Rudling, Thomas S Scanlan
1Metabolism Unit, Center for Metabolism and Endocrinology, Department of Medicine, and Molecular Nutrition Unit, Center for Nutrition and Toxicology, NOVUM, Karolinska Institute at Karolinska University Hospital-Huddinge, SE-141 86 Stockholm, Sweden.
Abstract:
Thyroid hormones [predominantly 3,5,3'-triiodo-L-thyronine (T3)] regulate cholesterol and lipoprotein metabolism, but cardiac effects restrict their use as hypolipidemic drugs. T3 binds to thyroid hormone receptors (TRs) alpha and beta. TRbeta is the predominant isoform in liver, whereas T3 effects on heart rate are mediated mostly by TRalpha. Drugs that target TRbeta or exhibit tissue-selective uptake may improve plasma lipid levels while sparing the heart. Here, we asked how the TRbeta- and liver uptake-selective agonist GC-1 influences cholesterol and triglyceride metabolism in euthyroid mice. GC-1 treatment reduced serum cholesterol levels by 25% and serum triglycerides by 75% in chow-fed mice and also attenuated diet-induced hypercholesterolemia. GC-1 reduced plasma high-density lipoprotein cholesterol levels; increased expression of the hepatic high-density lipoprotein receptor, SR-BI; stimulated activity of cholesterol 7alpha-hydroxylase; and increased fecal excretion of bile acids. Collectively, these results suggest that GC-1 stimulates important steps in reverse cholesterol transport. Use of TRbeta and uptake selective agonists such as GC-1 should be further explored as a strategy to improve lipid metabolism in dyslipoproteinemia.
Insights
The thyroid hormone analog GC-1 effectively lowers cholesterol and triglycerides by targeting the liver, offering a potential treatment for lipid disorders without cardiac side effects.
Area of Science:
- Endocrinology
- Metabolic research
- Pharmacology
Background:
- Thyroid hormones (like 3,5,3'-triiodo-L-thyronine, T3) regulate lipid metabolism.
- Cardiac side effects limit T3's use as a hypolipidemic drug.
- Thyroid hormone receptors (TRs) alpha and beta mediate T3's effects, with TRbeta predominant in the liver.
Purpose of the Study:
- To investigate the effects of the TRbeta- and liver uptake-selective agonist GC-1 on cholesterol and triglyceride metabolism.
- To assess GC-1's potential for improving lipid profiles while minimizing cardiac impact.
Main Methods:
- Treatment of euthyroid mice with the selective agonist GC-1.
- Analysis of serum cholesterol and triglyceride levels.
- Evaluation of high-density lipoprotein (HDL) receptor expression (SR-BI), cholesterol 7alpha-hydroxylase activity, and bile acid excretion.
Main Results:
- GC-1 reduced serum cholesterol by 25% and triglycerides by 75% in mice on a standard diet.
- GC-1 attenuated diet-induced hypercholesterolemia.
- GC-1 increased hepatic SR-BI expression, stimulated cholesterol 7alpha-hydroxylase, and enhanced fecal bile acid excretion, indicating improved reverse cholesterol transport.
Conclusions:
- GC-1 effectively improves lipid metabolism by stimulating key steps in reverse cholesterol transport.
- TRbeta-selective agonists like GC-1 represent a promising strategy for treating dyslipoproteinemia with reduced cardiac risk.
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