title: Thyroid hormone receptor agonists reduce serum cholesterol independent of the LDL receptor.
abstract: The majority of cholesterol reduction therapies, such as the statin drugs, work primarily by inducing the expression of hepatic low-density lipoprotein receptors (LDLRs), rendering these therapeutics only partially effective in animals lacking LDLRs. Although thyroid hormones and their synthetic derivatives, often referred to as thyromimetics, have been clearly shown to reduce serum cholesterol levels, this action has generally been attributed to their ability to increase expression of hepatic LDLRs. Here we show for the first time that the thyroid hormone T(3) and the thyroid hormone receptor-β selective agonists GC-1 and KB2115 are capable of markedly reducing serum cholesterol in mice devoid of functional LDLRs by inducing Cyp7a1 expression and stimulating the conversion and excretion of cholesterol as bile acids. Based on this LDLR-independent mechanism, thyromimetics such as GC-1 and KB2115 may represent promising cholesterol-lowering therapeutics for the treatment of diseases such as homozygous familial hypercholesterolemia, a rare genetic disorder caused by a complete lack of functional LDLRs, for which there are limited treatment options because most therapeutics are only minimally effective.
authors.affiliation: Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77204, USA.
authors.forename: Jean Z
authors.initials: JZ
authors.lastname: Lin
authors.forename: Alexandro J
authors.initials: AJ
authors.lastname: Martagón
authors.forename: Willa A
authors.initials: WA
authors.lastname: Hsueh
authors.forename: John D
authors.initials: JD
authors.lastname: Baxter
authors.forename: Jan-Åke
authors.initials: JÅ
authors.lastname: Gustafsson
authors.forename: Paul
authors.initials: P
authors.lastname: Webb
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Phillips
mesh_terms: D000085:Acetates / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism; D002784:Cholesterol / Q000097:blood*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism; D005243:Feces; D008074:Lipoproteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010636:Phenols / Q000494:pharmacology; D011973:Receptors, LDL / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000819:agonists*; D037042:Thyroid Hormone Receptors beta / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D014284:Triiodothyronine / Q000378:metabolism
chemical_list: C526273:3-((3,5-dibromo-4-(4-hydroxy-3-(1-methylethyl)phenoxy)phenyl)amino)-3-oxopropanoic acid; D000085:Acetates; D000813:Anilides; D001055:Apolipoproteins B; C413355:GC 1 compound; D008074:Lipoproteins; D010636:Phenols; D011973:Receptors, LDL; D011988:Receptors, Thyroid Hormone; D037042:Thyroid Hormone Receptors beta; D014280:Triglycerides; D014284:Triiodothyronine; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase; C502772:Cyp7a1 protein, mouse