Thyroid hormones [predominantly 3,5,3-triiodo-L-thyronine (T3)] regulate cholesterol and lipoprotein metabolism, but cardiac effects restrict their use as hypolipidemic drugs. T 3 binds to thyroid hormone receptors (TRs) ␣ and ␤. TR␤ is the predominant isoform in liver, whereas T 3 effects on heart rate are mediated mostly by TR␣. Drugs that target TR␤ or exhibit tissue-selective uptake may improve plasma lipid levels while sparing the heart. Here, we asked how the TR␤-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 dietinduced 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␣-hydroxylase; and increased fecal excretion of bile acids. Collectively, these results suggest that GC-1 stimulates important steps in reverse cholesterol transport. Use of TR␤ and uptake selective agonists such as GC-1 should be further explored as a strategy to improve lipid metabolism in dyslipoproteinemia.bile acid ͉ lipoprotein ͉ triglycerides ͉ thyroid hormone ͉ selective modulation

The described system should be of value in studies where detailed lipoprotein analysis is warranted and particularly when significant sample series with small volumes are available. Our data also suggest that there is a 4-5.5-fold concentration gradient between plasma and IF for the three major plasma lipoproteins.