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 (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.
Johansson
Lisen
L
Metabolism 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.
Rudling
Mats
M
Scanlan
Thomas S
TS
Lundåsen
Thomas
T
Webb
Paul
P
Baxter
John
J
Angelin
Bo
B
Parini
Paolo
P
D000085:Acetates / Q000494:pharmacology* / Q000627:therapeutic use; D000704:Analysis of Variance; D000818:Animals; D001647:Bile Acids and Salts / Q000032:analysis; D018955:CD36 Antigens; D002318:Cardiovascular Diseases / Q000517:prevention & control*; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism; D005243:Feces / Q000737:chemistry; D005786:Gene Expression Regulation / Q000187:drug effects*; D006937:Hypercholesterolemia / Q000188:drug therapy*; D015151:Immunoblotting; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010636:Phenols / Q000494:pharmacology* / Q000627:therapeutic use; D010647:Phenyl Ethers / Q000494:pharmacology; D010648:Phenylacetates / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000378:metabolism; D051116:Receptors, Scavenger; D020133:Reverse Transcriptase Polymerase Chain Reaction; D037042:Thyroid Hormone Receptors beta / Q000819:agonists* / Q000378:metabolism; D014280:Triglycerides / Q000097:blood / Q000378:metabolism; D014284:Triiodothyronine / Q000378:metabolism*
D000085:Acetates; D001647:Bile Acids and Salts; D018955:CD36 Antigens; C413355:GC 1 compound; C478108:KB 141; D010636:Phenols; D010647:Phenyl Ethers; D010648:Phenylacetates; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; D037042:Thyroid Hormone Receptors beta; D014280:Triglycerides; D014284:Triiodothyronine; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase