Selective thyroid receptor modulation by GC-1 reduces serum lipids and stimulates steps of reverse cholesterol transport in euthyroid mice

Thyroid hormones [predominantly 3,5,3'-triiodo-L-thyronine (T-3)] regulate cholesterol and lipoprotein metabolism, but cardiac effects restrict their use as hypolipidemic drugs. T3 binds to thyroid hormone receptors (TRs) alpha and beta. TR beta is the predominant isoform in liver, whereas T3 effects on heart rate are mediated mostly by TR alpha. Drugs that target TR beta or exhibit tissue-selective uptake may improve plasma lipid levels while sparing the heart. Here, we asked how the TR beta- 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 7 alpha-hydroxylase; and increased fecal excretion of bile acids. Collectively, these results suggest that GC-1 stimulates important steps in reverse cholesterol transport. Use of TRIS and uptake selective agonists such as GC-1 should be further explored as a strategy to improve lipid metabolism in dyslipoproteinemia.